JP2010526850A - Novel aromatic heterocyclic carboxylic acid amide derivatives useful as potassium channel regulators - Google Patents

Abstract

  The present invention has been found to be a potent modulator of potassium channels and is therefore a valuable candidate for treating a wide variety of diseases or disorders, such as diseases or disorders that respond to potassium channel modulation. ) Novel aromatic heterocyclic carboxylic acid amide derivatives.

Description

  The present invention is a novel fragrance that has been found to be a potent modulator of ion channels and is therefore a valuable candidate for treating a wide variety of diseases or disorders, such as diseases or disorders that respond to ion channel modulation. Group heterocyclic carboxylic acid amide derivatives.

  Ion channels are cellular proteins that regulate the flow of ions through the cell membrane of all cells and are classified by their selective permeability to different ions (potassium, chloride, sodium, etc.). Potassium channels, the largest and most diverse subgroup of ion channels, selectively allow potassium ions to pass through, thus primarily controlling the resting membrane potential of cells and / or regulating their excitability levels.

  Impaired dysfunction of potassium channels, as well as other ion channels, results in impaired cellular control leading to changes in physiological functions and disease states. Ion channel blockers and openers are used in pharmacological treatment of a wide range of pathological diseases, due to their ability to modulate ion channel function and / or restore ion channel activity in acquired or inherited channel abnormalities. It has the potential to address a wider range of therapeutic indications. For example, the main indications for potassium channel openers include a wide variety of conditions such as diabetes, arterial hypertension, cardiovascular disease, urinary incontinence, atrial fibrillation, epilepsy, pain and cancer.

  Among the many potassium channel types, the high conductance calcium activated potassium channel subtype is an obvious site for pharmacological intervention and for the development of new potassium channel modulators. The physiological role of potassium channels is in the nervous system, where they are neuroexcitatory, important regulators of neurotransmitter release, as well as the tension of blood vessels, bronchial trachea, urethra, uterus or gastrointestinal musculature. It has been studied especially in smooth muscle, which is very important for regulation.

  When these implications are shown, small drugs with BK opening characteristics are muscular and neurological such as asthma, urinary incontinence and bladder spasm, gastrointestinal locomotor hyperactivity, psychosis, post-stroke neuroprotection, convulsions, anxiety and pain. It may have a strong potential to influence and regulate many causal relationships for sexual overexcitation. As far as the cardiovascular system is concerned, the physiological function of these ion channels presents a basic steady state mechanism that regulates vascular depolarization, vasoconstriction and intravascular pressure increase, and The development of selective activators is likely to be a potential pharmacological treatment for angiopathy, including hypertension, erectile dysfunction, coronary artery disease, and vascular complications associated with diabetes or hypercholesterolemia. It is done.

  WO 2007/044724 describes certain N-tetrazolylphenylcarboxamide derivatives useful as PIM-1 and PIM-3 protein kinase inhibitors. However, the aromatic heterocyclic carboxylic acid amide derivatives of the present invention are not described, and certainly their use as potassium channel regulators is not suggested.

  It is an object of the present invention to provide novel aromatic heterocyclic carboxylic acid amide derivatives useful as ion channel modifiers.

（式中、
Ｘは、アルキル、シクロアルキル、アルケニル、アルキニル、メトキシイミノメチル、アミノ、Ｎ−アルキル−アミノ、Ｎ，Ｎ−ジアルキル−アミノ、Ｎ−アリール−アミノ、Ｎ，Ｎ−ジアリール−アミノ、アルキル−スルホニル−アミノ、アリール−スルホニル−アミノ、アルキル−カルボニル−アミノ、アリール−カルボニル−アミノ、フェニル、又はイミダゾリル、２−オキソピロリジン−１−イル、ピペリジニル、モルホリン−４−イル及びピリジニルから選択される５員若しくは６員複素環基を表し、これらのフェニル及び複素環基は、アルキル、ハロ、トリフルオロメチル、シアノ、ヒドロキシ、フェニル及びアルコキシ−カルボニルからなる群から選択される置換基で１回若しくは複数回場合によって置換されており；
Ｌは、存在せず（すなわち、共有結合を表し）、又は連結基−ＣＨ_２−若しくは−ＣＯＮＨ−を表し；
ＨＥＴは、フラニル、チエニル、オキサゾリル、チアゾリル、ピラゾリル及びトリアゾリルから選択される５員芳香族複素環基を表し、この複素環基は、アルキル、ハロ、トリフルオロメチル及びシアノからなる群から選択される置換基で１回若しくは複数回場合によって置換されており；
Ｒ^１は、テトラゾリル、テトラゾリル−アルコキシ、Ｎ−フェニル−カルバモイル、アルキル−スルホニル−アミノ−カルボニル、Ｎ−アルキル−スルホニル−カルボキサミド、Ｎ−フェニル−スルホニル−カルボキサミド、カルボキシ、Ｎ−シアノ−カルボキサミド、スルファモイル、スルホン酸、スルホン酸アルキルエステル、スルホン酸フェニルエステル、又は５−オキソ−４，５−ジヒドロ−［１，２，４］オキサジアゾール−３−イル及び５−チオキソ−４，５−ジヒドロ−［１，２，４］オキサジアゾール−３−イルから選択されるオキサジアゾリルオキソ−若しくはチオ−誘導体を表し；
Ｒ^２は、ハロ又はトリフルオロメチルを表し；
Ｒ^３は、水素、ハロ、トリフルオロメチル、アミノ、Ｎ−アルキル−アミノ、Ｎ，Ｎ−ジアルキル−アミノ、ピペリジニル又はモルホリニルを表す）、立体異性体若しくはその立体異性体の混合物、又はその医薬として許容できる付加塩によって特徴付けることができる。 The aromatic heterocyclic carboxylic acid amide derivatives of the present invention have the formula I

(Where
X is alkyl, cycloalkyl, alkenyl, alkynyl, methoxyiminomethyl, amino, N-alkyl-amino, N, N-dialkyl-amino, N-aryl-amino, N, N-diaryl-amino, alkyl-sulfonyl- 5-membered selected from amino, aryl-sulfonyl-amino, alkyl-carbonyl-amino, aryl-carbonyl-amino, phenyl or imidazolyl, 2-oxopyrrolidin-1-yl, piperidinyl, morpholin-4-yl and pyridinyl Represents a 6-membered heterocyclic group, and these phenyl and heterocyclic groups are one or more times with a substituent selected from the group consisting of alkyl, halo, trifluoromethyl, cyano, hydroxy, phenyl and alkoxy-carbonyl Has been replaced by;
L is absent (ie represents a covalent bond) or represents a linking group —CH ₂ — or —CONH—;
HET represents a 5-membered aromatic heterocyclic group selected from furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl and triazolyl, which heterocyclic group is selected from the group consisting of alkyl, halo, trifluoromethyl and cyano Optionally substituted one or more times with a substituent;
R ¹ is tetrazolyl, tetrazolyl-alkoxy, N-phenyl-carbamoyl, alkyl-sulfonyl-amino-carbonyl, N-alkyl-sulfonyl-carboxamide, N-phenyl-sulfonyl-carboxamide, carboxy, N-cyano-carboxamide, sulfamoyl, Sulfonic acids, sulfonic acid alkyl esters, sulfonic acid phenyl esters, or 5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl and 5-thioxo-4,5-dihydro- [ Represents an oxadiazolyloxo- or thio-derivative selected from 1,2,4] oxadiazol-3-yl;
R ² represents halo or trifluoromethyl;
R ³ represents hydrogen, halo, trifluoromethyl, amino, N-alkyl-amino, N, N-dialkyl-amino, piperidinyl or morpholinyl), a stereoisomer or a mixture of stereoisomers thereof, or a medicament thereof It can be characterized by an acceptable addition salt.

  In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of an aromatic heterocyclic carboxylic acid amide derivative of the present invention.

  In a third aspect, the present invention relates to the use of the aromatic heterocyclic carboxylic acid amide derivatives of the present invention for the manufacture of a pharmaceutical composition.

In a further aspect, the present invention provides a method for treating, preventing or alleviating a disease, disorder or condition responsive to the regulation of potassium channels in the body of an animal, including humans, in such animals in need thereof. There is provided a method comprising administering to a living body a therapeutically effective amount of an aromatic heterocyclic carboxylic acid amide derivative of the present invention.
Other objects of the invention will be apparent to the person skilled in the art from the following detailed description and examples.

FIG. 2 is a graph showing conductance (μS) versus membrane potential (mV) in the absence of Compound 2 (control) and in the presence of 0.01-31.6 μM of Compound 2. FIG. FIG. 6 is a graph showing the concentration-response relationship for the left shift of BK _Ca -activation curve induced by Compound 2, ie ΔV (mV) vs. log [c] (M). The calculated EC50 value is 2.4 μM and the maximum left shift for the BK-activation curve is -94 mV. FIG. 2 is a graph showing conductance (μS) versus membrane potential (mV) in the absence of Compound 1 (control) and in the presence of 0.01-31.6 μM of Compound 1. FIG. FIG. 6 is a graph showing the concentration-response relationship for the left shift of BK _Ca -activation curve induced by Compound 1, ie ΔV (mV) vs log [c] (M). The calculated EC50 value is 4.4 μM and the maximum left shift for the BK-activation curve is -88 mV. FIG. 5 is a graph showing conductance (μS) versus membrane potential (mV) in the absence of compound 9 (control) and in the presence of 0.01-31.6 μM of compound 9. FIG. 10 is a graph showing the concentration-response relationship for the BK _Ca -activation curve induced by Compound 9; ie, the left shift of ΔV (mV) versus log [c] (M). The calculated EC50 value is 0.97 μM and the maximum left shift for the BK-activation curve is -99 mV.

（式中、
Ｘは、アルキル、シクロアルキル、アルケニル、アルキニル、メトキシイミノメチル、アミノ、Ｎ−アルキル−アミノ、Ｎ，Ｎ−ジアルキル−アミノ、Ｎ−アリール−アミノ、Ｎ，Ｎ−ジアリール−アミノ、アルキル−スルホニル−アミノ、アリール−スルホニル−アミノ、アルキル−カルボニル−アミノ、アリール−カルボニル−アミノ、フェニル、又はイミダゾリル、２−オキソピロリジン−１−イル、ピペリジニル、モルホリン−４−イル及びピリジニルから選択される５員若しくは６員複素環基を表し、これらのフェニル及び複素環基は、アルキル、ハロ、トリフルオロメチル、シアノ、ヒドロキシ、フェニル及びアルコキシ−カルボニルからなる群から選択される置換基で１回若しくは複数回場合によって置換されており；
Ｌは、存在せず（すなわち、共有結合を表し）、又は連結基−ＣＨ_２−若しくは−ＣＯＮＨ−を表し；
ＨＥＴは、フラニル、チエニル、オキサゾリル、チアゾリル、ピラゾリル及びトリアゾリルから選択される５員芳香族複素環基を表し、この複素環基は、アルキル、ハロ、トリフルオロメチル及びシアノからなる群から選択される置換基で１回若しくは複数回場合によって置換されており；
Ｒ^１は、テトラゾリル、テトラゾリル−アルコキシ、Ｎ−フェニル−カルバモイル、アルキル−スルホニル−アミノ−カルボニル、Ｎ−アルキル−スルホニル−カルボキサミド、Ｎ−フェニル−スルホニル−カルボキサミド、カルボキシ、Ｎ−シアノ−カルボキサミド、スルファモイル、スルホン酸、スルホン酸アルキルエステル、スルホン酸フェニルエステル、又は５−オキソ−４，５−ジヒドロ−［１，２，４］オキサジアゾール−３−イル及び５−チオキソ−４，５−ジヒドロ−［１，２，４］オキサジアゾール−３−イルから選択されるオキサジアゾリルオキソ−若しくはチオ−誘導体を表し；
Ｒ^２は、ハロ又はトリフルオロメチルを表し；
Ｒ^３は、水素、ハロ、トリフルオロメチル、アミノ、Ｎ−アルキル−アミノ、Ｎ，Ｎ−ジアルキル−アミノ、ピペリジニル又はモルホリニルを表す）、立体異性体若しくはその立体異性体の混合物、又はその医薬として許容できる付加塩を提供する。 In its first aspect, the present invention provides a novel aromatic heterocyclic carboxylic acid amide derivative of formula I

(Where
X is alkyl, cycloalkyl, alkenyl, alkynyl, methoxyiminomethyl, amino, N-alkyl-amino, N, N-dialkyl-amino, N-aryl-amino, N, N-diaryl-amino, alkyl-sulfonyl- 5-membered or selected from amino, aryl-sulfonyl-amino, alkyl-carbonyl-amino, aryl-carbonyl-amino, phenyl or imidazolyl, 2-oxopyrrolidin-1-yl, piperidinyl, morpholin-4-yl and pyridinyl Represents a 6-membered heterocyclic group, and these phenyl and heterocyclic groups are one or more times with a substituent selected from the group consisting of alkyl, halo, trifluoromethyl, cyano, hydroxy, phenyl and alkoxy-carbonyl Has been replaced by;
L is absent (ie represents a covalent bond) or represents a linking group —CH ₂ — or —CONH—;
HET represents a 5-membered aromatic heterocyclic group selected from furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl and triazolyl, which heterocyclic group is selected from the group consisting of alkyl, halo, trifluoromethyl and cyano Optionally substituted one or more times with a substituent;
R ¹ is tetrazolyl, tetrazolyl-alkoxy, N-phenyl-carbamoyl, alkyl-sulfonyl-amino-carbonyl, N-alkyl-sulfonyl-carboxamide, N-phenyl-sulfonyl-carboxamide, carboxy, N-cyano-carboxamide, sulfamoyl, Sulfonic acids, sulfonic acid alkyl esters, sulfonic acid phenyl esters, or 5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl and 5-thioxo-4,5-dihydro- [ Represents an oxadiazolyloxo- or thio-derivative selected from 1,2,4] oxadiazol-3-yl;
R ² represents halo or trifluoromethyl;
R ³ represents hydrogen, halo, trifluoromethyl, amino, N-alkyl-amino, N, N-dialkyl-amino, piperidinyl or morpholinyl), a stereoisomer or a mixture of stereoisomers thereof, or a medicament thereof Provide an acceptable addition salt.

In a preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention is a compound of formula I wherein X is alkyl, cycloalkyl, alkenyl, alkynyl, methoxy-iminomethyl (ie, the formula CH ₃ O— N = C-substituent), amino, N-alkyl-amino, N, N-dialkyl-amino, N-aryl-amino, N, N-diaryl-amino, alkyl-sulfonyl-amino, aryl-sulfonyl-amino Represents a 5-membered or 6-membered heterocyclic group selected from alkyl-carbonyl-amino, aryl-carbonyl-amino, phenyl, or imidazolyl, 2-oxopyrrolidin-1-yl, piperidinyl, morpholin-4-yl and pyridinyl These phenyl and heterocyclic groups are alkyl, halo, trifluoromethyl Cyano, hydroxy, phenyl, and alkoxy - is are optionally substituted one or more times with substituents selected from the group consisting of carbonyl), or acceptable addition salt thereof pharmaceutical.

In more preferred embodiments, X is alkyl, alkenyl, alkynyl, methoxy-iminomethyl (ie, a substituent of formula CH ₃ O—N═C—), amino, N-alkyl-amino, N, N-dialkyl-amino. N-aryl-amino, N, N-diaryl-amino, alkyl-sulfonyl-amino, aryl-sulfonyl-amino, alkyl-carbonyl-amino, aryl-carbonyl-amino, phenyl or imidazolyl, 2-oxopyrrolidine-1 Represents a 5- or 6-membered heterocyclic group selected from -yl and morpholin-4-yl, these phenyl and heterocyclic groups selected from the group consisting of alkyl, halo, trifluoromethyl, cyano, hydroxy and phenyl Optionally substituted once or multiple times with .

  In other more preferred embodiments, X is alkyl, cycloalkyl, alkenyl, alkynyl, methoxyiminomethyl, amino, N-alkyl-amino, N, N-dialkyl-amino, N-aryl-amino, N, N- Represents diaryl-amino, alkyl-sulfonyl-amino, aryl-sulfonyl-amino, alkyl-carbonyl-amino or aryl-carbonyl-amino.

  In a third more preferred embodiment, X is alkyl, alkenyl, alkynyl, methoxyiminomethyl, amino, N-alkyl-amino, N, N-dialkyl-amino, N-aryl-amino, N, N-diaryl- Represents amino, alkyl-sulfonyl-amino, aryl-sulfonyl-amino, alkyl-carbonyl-amino or aryl-carbonyl-amino.

  In a fourth more preferred embodiment X represents alkyl or cycloalkyl.

  In a fifth more preferred embodiment X represents cycloalkyl, and in particular cyclopentyl.

  In a sixth more preferred embodiment, X represents phenyl or a 5- or 6-membered heterocyclic group selected from imidazolyl, 2-oxopyrrolidin-1-yl, piperidinyl, morpholin-4-yl and pyridinyl, The phenyl and heterocyclic groups are optionally substituted one or more times with a substituent selected from the group consisting of alkyl, halo, trifluoromethyl, cyano, hydroxy, phenyl and alkoxy-carbonyl.

  In a seventh more preferred embodiment, X represents phenyl or a 5- or 6-membered heterocyclic group selected from imidazolyl, 2-oxopyrrolidin-1-yl and morpholin-4-yl, The ring group is optionally substituted one or more times with a substituent selected from the group consisting of alkyl, halo, trifluoromethyl, cyano, hydroxy and phenyl.

  In an eighth more preferred embodiment X represents phenyl, piperidinyl, morpholin-4-yl or pyridinyl, which phenyl and heterocyclic groups are optionally substituted with halo, trifluoromethyl or alkoxy-carbonyl. .

  In a ninth more preferred embodiment, X represents phenyl, piperidinyl or pyridinyl, wherein the phenyl, piperidinyl and pyridinyl groups are optionally substituted with halo, trifluoromethyl or alkoxy-carbonyl.

  In a tenth more preferred embodiment, X represents phenyl, piperidinyl, morpholin-4-yl or pyridinyl, which phenyl and heterocyclic groups are optionally substituted with chloro, bromo, trifluoromethyl or isobutoxy-carbonyl. ing.

  In an eleventh more preferred embodiment X represents phenyl, piperidinyl, morpholin-4-yl or pyridinyl, which phenyl and heterocyclic groups are optionally substituted with chloro, bromo, trifluoromethyl or isobutoxy-carbonyl. ing.

  In a twelfth more preferred embodiment, X represents phenyl, which is optionally substituted once or twice with a substituent selected from the group consisting of alkyl, halo, trifluoromethyl, cyano, hydroxy and phenyl. ing.

  In a thirteenth more preferred embodiment X represents phenyl substituted with halo, trifluoromethyl, cyano, hydroxy and phenyl.

  In a fourteenth more preferred embodiment X represents phenyl substituted with halo, in particular chloro or bromo, or trifluoromethyl.

  In a fifteenth more preferred embodiment, X represents a 5- or 6-membered heterocyclic group selected from imidazolyl, 2-oxopyrrolidin-1-yl and morpholin-4-yl, wherein the heterocyclic group is alkyl Optionally substituted with halo, trifluoromethyl, cyano, hydroxy or phenyl.

  In a sixteenth more preferred embodiment, X represents morpholin-4-yl.

  In a seventeenth more preferred embodiment X represents an imidazolyl group, which is optionally substituted with alkyl, halo, trifluoromethyl, cyano, hydroxy or phenyl.

  In an eighteenth more preferred embodiment X represents a 2-oxopyrrolidin-1-yl group, which 2-oxopyrrolidin-1-yl group is alkyl, halo, trifluoromethyl, cyano, hydroxy or phenyl. Sometimes replaced.

  In a nineteenth more preferred embodiment, X represents a morpholin-4-yl group, which morpholin-4-yl group is optionally substituted with alkyl, halo, trifluoromethyl, cyano, hydroxy or phenyl. .

In other preferred embodiments, the aromatic heterocyclic carboxylic acid amide derivative of the invention is a compound of formula I wherein L is absent (ie represents a covalent bond) or a linking group —CH ₂ -Or -CONH-) or a pharmaceutically acceptable addition salt thereof.

In a more preferred embodiment, L is absent (ie represents a covalent bond) or represents a linking group —CH ₂ —.

  In other more preferred embodiments, L is absent (ie represents a covalent bond).

In a third more preferred embodiment, L represents a linking group —CH ₂ —.

  In a fourth more preferred embodiment, L represents a linking group -CONH-.

  In a third preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the invention is a compound of formula I wherein HET is selected from furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl and triazolyl Represents an aromatic heterocyclic group, the heterocyclic group optionally substituted one or more times with a substituent selected from the group consisting of alkyl, halo and trifluoromethyl) or a pharmaceutically acceptable addition thereof Salt.

  In a more preferred embodiment, HET represents a 5-membered aromatic heterocyclic group selected from furanyl, oxazolyl, thiazolyl, pyrazolyl and triazolyl, wherein the heterocyclic group is selected from the group consisting of alkyl, halo and trifluoromethyl. Optionally substituted once or multiple times with a substituent.

  In another more preferred embodiment, HET represents furanyl optionally substituted one or more times with a substituent selected from the group consisting of alkyl, especially methyl, halo and trifluoromethyl.

  In a third more preferred embodiment, HET represents oxazolyl optionally substituted one or more times with a substituent selected from the group consisting of alkyl, especially methyl, halo and trifluoromethyl.

  In a fourth more preferred embodiment, HET represents thiazolyl optionally substituted one or more times with a substituent selected from the group consisting of alkyl, especially methyl, halo and trifluoromethyl.

  In a fifth more preferred embodiment, HET represents pyrazolyl optionally substituted one or more times with a substituent selected from the group consisting of alkyl, especially methyl, halo and trifluoromethyl.

  In a sixth more preferred embodiment, HET represents a triazolyl group, and in particular 1,2,3-triazolyl, wherein the heterocyclic group is a substituent selected from the group consisting of alkyl, especially methyl, halo and trifluoromethyl. Optionally substituted one or more times with a group.

  In a seventh more preferred embodiment, HET is furan-2,4-diyl, thien-2,4-diyl, oxazole-2,4-diyl, thiazole-2,4-diyl, pyrazole-2,4- Represents a 5-membered aromatic heterocyclic group selected from diyl and 1,2,3-triazol-1,4-diyl, which heterocyclic group is selected from the group consisting of alkyl, in particular methyl, halo and trifluoromethyl. Optionally substituted once or multiple times.

  In an even more preferred embodiment, the 5-membered aromatic heterocyclic group is optionally substituted with alkyl, particularly methyl, halo or trifluoromethyl.

  In an even more preferred embodiment, the 5-membered aromatic heterocyclic group is optionally substituted with alkyl, particularly methyl, or trifluoromethyl.

  In an even more preferred embodiment, the 5-membered aromatic heterocyclic group is optionally substituted with methyl or trifluoromethyl.

In a fourth preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention is a compound of formula I wherein R ¹ is tetrazolyl, tetrazolyl-alkoxy, N-phenyl-carbamoyl, alkyl-sulfonyl- Amino-carbonyl, N-alkyl-sulfonyl-carboxamide, N-phenyl-sulfonyl-carboxamide, carboxy, N-cyano-carboxamide, sulfamoyl, sulfonic acid, sulfonic acid alkyl ester, sulfonic acid phenyl ester, or 5-oxo-4, Oxadiazolyl selected from 5-dihydro- [1,2,4] oxadiazol-3-yl and 5-thioxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl Oxo- or thio-derivative) or pharmaceutically acceptable Addition salt.

In a more preferred embodiment, R ¹ represents a tetrazolyl group, and in particular 1H-tetrazol-5-yl.

In another more preferred embodiment, R ¹ represents a tetrazolyl-alkoxy group, and in particular 1H-tetrazol-5-yl-methoxy.

In a third more preferred embodiment, R ¹ represents N-phenyl-carbamoyl.

In a fourth more preferred embodiment, R ¹ represents an alkyl-sulfonyl-amino-carbonyl group, and in particular methyl-sulfonyl-amino-carbonyl.

In a fifth more preferred embodiment, R ¹ represents an N-alkyl-sulfonyl-carboxamide group, and in particular N-methyl-sulfonyl-carboxamide.

In a sixth more preferred embodiment, R ¹ represents N-phenyl-sulfonyl-carboxamide.

In a seventh more preferred embodiment, R ¹ represents carboxy.

In an eighth more preferred embodiment, R ¹ represents N-cyano-carboxamide.

In a ninth more preferred embodiment, R ¹ represents sulfamoyl.

In a tenth more preferred embodiment, R ¹ represents sulfonic acid.

In an eleventh more preferred embodiment, R ¹ represents a sulfonic acid alkyl ester, and particularly a sulfonic acid methyl ester.

In a twelfth more preferred embodiment, R ¹ represents sulfonic acid phenyl ester.

In a thirteenth more preferred embodiment, R ¹ represents 5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl.

In a fourteenth more preferred embodiment, R ¹ represents 5-thioxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl.

In a fifth preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention is a compound of formula I (wherein R ² represents halo or trifluoromethyl) or a pharmaceutically acceptable addition salt thereof. It is.

In a more preferred embodiment, R ² represents halo.

In an even more preferred embodiment, R ² represents fluoro or chloro.

In a sixth preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention comprises a compound of formula I wherein R ³ is hydrogen, halo, trifluoromethyl, amino, N-alkyl-amino, N, N-dialkyl-amino, piperidinyl or morpholinyl) or a pharmaceutically acceptable addition salt thereof.

In a more preferred embodiment, R ³ represents hydrogen, halo or trifluoromethyl.

In another more preferred embodiment, R ³ represents hydrogen, halo, N, N-dialkyl-amino, piperidinyl or morpholinyl.

In a more preferred embodiment, R ³ represents hydrogen or halo.

In an even more preferred embodiment, R ³ represents hydrogen.

In an even more preferred embodiment R ³ represents halo, in particular fluoro.

In another more preferred embodiment, R ³ represents hydrogen or fluoro.

In an even more preferred embodiment R ³ represents N, N-dialkyl-amino, and in particular N, N-dimethyl-amino; piperidinyl or morpholinyl.

In the most preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention comprises
5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
1- (4-Chloro-phenyl) -5-trifluoromethyl-1H-pyrazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
1- (4-Bromo-benzyl) -5-methyl-1H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide ;
5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid (5-chloro-2-phenylcarbamoyl-phenyl) -amide;
5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid (5-chloro-2-methanesulfonylaminocarbonyl-phenyl) -amide;
4-chloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzenesulfonic acid;
5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (1H-tetrazol-5-ylmethoxy) -phenyl] -amide;
4,5-dichloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzenesulfonic acid;
4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
4-chloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzoic acid;
4-chloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzoylcyanamide;
5- (4-chloro-phenyl) -2-methyl-furan-3-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -4,5-difluoro-benzoic acid;
4,5-dichloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzenesulfonic acid methyl ester;
5-methyl-2-phenyl-2H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
5-trifluoromethyl-2- (4-trifluoromethyl-phenyl) -oxazole-4-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxa Diazol-3-yl) -phenyl] -amide;
5-trifluoromethyl-2- (4-trifluoromethyl-phenyl) -oxazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole) -3-yl) -phenyl] -amide;
5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [4,5-dichloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
5- (4-Chloro-phenyl) -2-methyl-furan-3-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole-3 -Yl) -phenyl] -amide;
2- (4-Chloro-benzyl) -thiazole-4-carboxylic acid [5-chloro-2- (5-oxo-2,5-dihydro- [1,2,4] oxadiazol-3-yl)- Phenyl] -amide;
1- (4-Bromo-benzyl) -5-methyl-1H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1, 2,4] oxadiazol-3-yl) -phenyl] -amide;
4-Methyl-2-morpholin-4-yl-thiazole-5-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl) ) -Phenyl] -amide;
4-methyl-2-morpholin-4-yl-thiazole-5-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
2- (3-Chloro-phenyl) -5-methyl-2H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1, 2,4] oxadiazol-3-yl) -phenyl] -amide;
4- {5- [5-Chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl) -phenylcarbamoyl] -4-methyl-thiazole-2 -Yl} -piperidine-1-carboxylic acid tert-butyl ester;
4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole) -3-yl) -phenyl] -amide;
5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-4-morpholin-4-yl-2- (5-oxo-4,5-dihydro- [1 , 2,4] oxadiazol-3-yl) -phenyl] -amide;
5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-4-dimethylamino-2- (5-oxo-4,5-dihydro- [1,2, 4] oxadiazol-3-yl) -phenyl] -amide;
5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole) -3-yl) -4-piperidin-1-yl-phenyl] -amide;
2- (3-Chloro-phenyl) -5-methyl-2H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide ;
4-methyl-2-pyridin-4-yl-thiazole-5-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole) -3-yl) -4-piperidin-1-yl-phenyl] -amide;
5- (cyclopentanecarbonyl-amino) -3-methyl-thiophene-2-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide; or 2,4-dichloro-6 -[(4-Methyl-2-morpholin-4-yl-thiazole-5-carbonyl) -amino] -benzoic acid;
Or a pharmaceutically acceptable addition salt thereof.

  Any combination of two or more embodiments described herein is considered within the scope of the present invention.

Definition of Substituents In the context of this invention an alkyl group refers to a monovalent saturated, straight or branched hydrocarbon chain. The hydrocarbon chain preferably contains 1 to 18 carbon atoms (C _1-18 -alkyl), more preferably 1 to 6 carbon atoms (C _1-6 -alkyl; lower alkyl). Preferably, pentyl, isopentyl, neopentyl, tertiary pentyl, hexyl and isohexyl are included. In a preferred embodiment, alkyl represents a C _1-4 -alkyl group and includes butyl, isobutyl, secondary butyl and tertiary butyl. In another preferred embodiment of the invention, alkyl represents a C _1-3 -alkyl group, which can in particular be methyl, ethyl, propyl or isopropyl.

In the context of this invention an alkenyl group refers to a straight or branched carbon chain containing one or more double bonds and includes di-enes, tri-enes and poly-enes. In preferred embodiments, the alkenyl groups of the present invention contain 2 to 8 carbon atoms (C _2-8 -alkenyl), more preferably contain 2 to 6 carbon atoms (C _2-6 -alkenyl), and at least Contains one double bond. In the most preferred embodiments, the alkenyl groups of the present invention are ethenyl; 1- or 2-propenyl (allyl); 1-, 2- or 3-butenyl, or 1,3-butadienyl; 1-, 2-, 3- 4-, 5-hexenyl, or 1,3-hexadienyl, or 1,3,5-hexatrienyl; 1-, 2-, 3-, 4-, 5-, 6-, or 7-octenyl, or 1 , 3-octadienyl, or 1,3,5-octatrienyl, or 1,3,5,7-octatetraenyl.

In the context of this invention an alkynyl group refers to a straight or branched carbon chain containing one or more triple bonds and includes di-ynes, tri-ynes and poly-ynes. In preferred embodiments, the alkynyl group of the invention contains 2 to 8 carbon atoms (C _2-8 -alkynyl), more preferably 2 to 6 carbon atoms (C _2-6 -alkynyl), and at least Contains one triple bond. In its most preferred embodiments, the alkynyl group of the present invention is ethynyl; 1- or 2-propynyl; 1-, 2- or 3-butynyl, or 1,3-butadiynyl; 1-, 2-, 3-, 4 -Pentynyl, or 1,3-pentadiynyl; 1-, 2-, 3-, 4- or 5-hexynyl, or 1,3-hexadiynyl, or 1,3,5-hexatriynyl; 1-, 2-, 3-, 4-, 5- or 6-heptynyl, or 1,3-heptodiinyl, or 1,3,5-heptotriinyl; 1-, 2-, 3-, 4-, 5-, 6- or 7-octynyl Or 1,3-octodiinyl, or 1,3,5-octotriynyl, or 1,3,5,7-octotetrinyl.

  In the context of this invention an N-alkyl-amino group refers to a (secondary) amino group, monosubstituted with an alkyl group as defined above.

  In the context of the present invention, an N-aryl-amino group refers to a (secondary) amino group, monosubstituted with an aryl group as defined below.

  In the context of the present invention, an N, N-dialkyl-amino group refers to a (tertiary) amino group disubstituted with an alkyl group as defined above.

  In the context of the present invention, an N, N-diaryl-amino group refers to a (tertiary) amino group, disubstituted with an aryl group as defined below.

In the context of this invention an alkyl-sulfonyl-amino group designates an “alkyl-SO ₂ —NH—” group, wherein alkyl is as defined above.

In the context of this invention an aryl-sulfonyl-amino group designates an “aryl-SO ₂ —NH—” group, wherein aryl is as defined below.

  In the context of this invention an alkyl-carbonyl-amino group designates an “alkyl-CO—NH—” group, wherein alkyl is as defined above.

  In the context of this invention an aryl-carbonyl-amino group designates an “aryl-CO—NH—” group, wherein aryl is as defined below.

  In the context of this invention alkoxy-carbonyl refers to an “alkoxy-CO—” group wherein alkoxy is as defined above.

  In the context of this invention halo represents fluoro, chloro, bromo or iodo.

  In the context of this invention an aryl group refers to a monocyclic or polycyclic aromatic hydrocarbon group. Examples of preferred aryl groups of the present invention include phenyl, indenyl, naphthyl, azulenyl, fluorenyl and anthracenyl. In the most preferred embodiment, the aryl group of the present invention is phenyl.

Pharmaceutically acceptable salts The aromatic heterocyclic carboxylic acid amide derivatives of the present invention can be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (ie physiologically) acceptable salts and pre- or prodrug forms of the aromatic heterocyclic carboxylic acid amide derivatives of the invention.

  Examples of pharmaceutically acceptable addition salts include, but are not limited to, hydrochloride, hydrobromide, nitrate, perchlorate, phosphate, sulfate, formate, acetate, aconite, ascorbine Acid salt, benzene sulfonate, benzoate, cinnamate, citrate, embonate, enanthate, fumarate, glutamate, glycolate, lactate, maleate, malonic acid Salt, mandelate, methanesulfonate, naphthalene-2-sulfonate, phthalate, salicylate, sorbate, stearate, succinate, tartrate, toluene-p-sulfonate, etc. Non-toxic inorganic and organic acid addition salts. Such salts can be formed by procedures well known and described in the art.

  Examples of the pharmaceutically acceptable cation salt of the aromatic heterocyclic carboxylic acid amide derivative of the present invention include, but are not limited to, sodium and potassium of the aromatic heterocyclic carboxylic acid amide derivative of the present invention containing an anionic group. , Calcium, magnesium, lithium and ammonium salts. Such chaotic salts can be formed by procedures well known and described in the art.

Stereoisomers It will be appreciated by those skilled in the art that the compounds of the present invention can exist in different stereoisomeric forms, including enantiomers, diastereomers, and geometric isomers (cis-trans isomers). Let's go. The present invention includes all such isomers and any mixtures thereof including racemic mixtures.

  Racemates can be resolved into optical enantiomers by known methods and techniques. One method for resolving racemates into optical enantiomers is based on chromatography on an optically active matrix. Thus, the racemates of the invention can be resolved into their optical enantiomers, for example by fractional crystallization of D- or L-salts (tartrate, mandelate or camphorsulfonate).

  Additional methods for resolving optical isomers are known in the art. Such methods are described by James J, Collet A, & Wilen S, “Enantiomers, Racemates, and Resolutions,” John Wiley and Sons, New York (1981). Is included.

  Optical active compounds can also be prepared from optically active starting materials or intermediates.

Methods of Preparation The compounds according to the invention can be prepared by conventional chemical synthesis methods, such as those described in the examples.

Bioactivity The aromatic heterocyclic carboxylic acid amide derivatives of the present invention have been found to have potassium channel modulating activity as measured by standard electrophysiological methods. Because of their activity in potassium channels, the aromatic heterocyclic carboxylic acid amide derivatives of the present invention are considered useful for the treatment of a wide range of diseases and conditions.

  In a specific embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention is a respiratory disease, epilepsy, convulsions, seizures, absence seizures, vasospasm, coronary artery spasm, motor neuron disease, myopathies, kidney Disease, polycystic kidney disease, bladder hyperexcitation, bladder spasticity, genitourinary disorder, urinary incontinence, outflow obstruction, erectile dysfunction, gastrointestinal disorders, gastrointestinal dysmotility disorder, gastrointestinal motility dysfunction, postoperative Bowel obstruction, constipation, gastroesophageal reflux disorder, secretory diarrhea, obstructive or inflammatory airway disease, ischemia, cerebral ischemia, ischemic heart disease, angina, coronary heart disease, ataxia, traumatic brain injury , Stroke, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, autism, anxiety, mood disorder, depression, manic depression, psychotic disorder, dementia, learning deficits, age-related memory forgetfulness, memory as well as Mental deficit, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), dysmenorrhea, sleep stroke disease, sleep disorder, sleep apnea, Raynaud's disease, intermittent claudication, Sjogren's syndrome, xerostomia, cardiovascular Sexual disorders, hypertension, myotonic dystrophy, myotonic dystrophy, spasticity, dry mouth, type II diabetes, hyperinsulinemia, premature birth, cancer, brain tumor, inflammatory bowel disease, irritable bowel syndrome, Treatment, prevention of colitis, Crohn's enteritis, immunosuppression, hearing loss, migraine, pain, neuropathic pain, inflammatory pain, trigeminal neuralgia, visual impairment, rhinorrhea, ocular hypertension (glaucoma) or alopecia Or it may be useful for mitigation.

  In a more preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention is a respiratory disease, urinary incontinence, erectile dysfunction, anxiety, epilepsy, psychosis, schizophrenia, bipolar disorder, depression, muscle atrophy. It is considered useful for the treatment, prevention or alleviation of lateral sclerosis (ALS), Parkinson's disease or pain.

  In another more preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention is for the treatment, prevention or alleviation of psychosis, schizophrenia, bipolar disorder, depression, epilepsy, Parkinson's disease or pain. It is considered useful.

  In a third more preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention comprises pain, mild or moderate or severe pain, acute, chronic or recurrent pain, pain due to migraine, surgery Treatment, prevention or alleviation of afterache, phantom limb pain, inflammatory pain, neuropathic pain, chronic headache, central pain, pain associated with diabetic neuropathy, pain associated with therapeutic neuralgia, or pain associated with peripheral nerve injury Considered useful for.

  In a fourth more preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention is useful for the treatment, prevention or alleviation of cardiac ischemia, ischemic heart disease, cardiac hypertrophy, cardiomyopathy or heart failure. Conceivable.

  In a fifth more preferred embodiment, the compounds of the invention are considered useful for the treatment, prevention or alleviation of cardiovascular disease. In a more preferred embodiment, the cardiovascular disease is atherosclerosis, ischemia / reperfusion, hypertension, restenosis, arterial inflammation, myocardial ischemia or ischemic heart disease.

  In a sixth more preferred embodiment, the compounds of the invention are considered useful for obtaining cardiac preconditioning. Preconditioning includes ischemic preconditioning and myocardial preconditioning to find short-term ischemic events before long-lasting ischemia begins. The compounds of the present invention are believed to have similar effects as preconditioning obtained by such ischemic events. Preconditioning protects against subsequent tissue damage resulting from long lasting ischemic events.

  In a seventh more preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention is considered useful for the treatment, prevention or alleviation of schizophrenia, depression or Parkinson's disease.

  In an eighth more preferred embodiment, the compounds of the invention are considered useful for the treatment, prevention or alleviation of obstructive or inflammatory airway diseases. In a more preferred embodiment, the obstructive or inflammatory airway disease is airway hypersensitivity; aluminosis, charcoal, asbestosis, asbestosis, puffy inhalation ptylosion, iron deposition, Pneumoconiosis such as silicosis, tobaccosis and cotton fiber inhalation pneumonia; chronic obstructive pulmonary disease (COPD), bronchitis; hatred of airway hypersensitivity or cystic fibrosis.

  In its most preferred embodiment, the obstructive airway disease is chronic obstructive pulmonary disease (COPD).

  In a ninth more preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention treats, prevents or reduces sexual dysfunction, including male erectile dysfunction, including male sexual dysfunction and female sexual dysfunction. Considered useful for.

  In an even more preferred embodiment, the aromatic heterocyclic carboxylic acid amide derivative of the present invention can be co-administered with a phosphodiesterase inhibitor, in particular a phosphodiesterase 5 (PED5) inhibitor such as, for example, suridenafil, tadalafil, vardenafil and dipyridamole or It can be co-administered with agents that enhance the polarization factor mediated response, particularly calcium dobesilate or similar 2,5-dihydroxybenzenesulfonate analogs.

  In the most preferred embodiments, the aromatic heterocyclic carboxylic acid amide derivatives of the present invention are used in combination therapy with sildenafil, tadalafil, vardenafil or calcium dobesilate.

  Currently, suitable dosages of the active pharmaceutical ingredient (API) range from about 0.1 to about 1000 mg API per day, more preferably from about 10 to about 500 mg API per day, most preferably from about 30 to about 100 mg API per day. It depends on the exact method of administration, the form in which it is administered, the indication being considered, the weight of the subject concerned and in particular the subject, as well as the preference and experience of the attending physician or veterinarian. Is intended to be.

  Preferred aromatic heterocyclic carboxylic acid amide derivatives of the present invention exhibit bioactivity in submicromolar and micromolar ranges, ie from less than 1 to about 100 μM.

Pharmaceutical Compositions In another aspect, the present invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of an aromatic heterocyclic carboxylic acid amide derivative of the present invention.

  The aromatic heterocyclic carboxylic acid amide derivatives of the present invention for use in therapy can be administered in the form of a raw chemical compound, but the active ingredient is optionally in the form of a physiologically acceptable salt. Alternatively, it is preferable to formulate the pharmaceutical composition together with a plurality of adjuvants, excipients, carriers, buffers, diluents, and / or other conventional pharmaceutical auxiliary substances.

  In preferred embodiments, the present invention relates to the aromatic heterocyclic carboxylic acid amide derivatives of the present invention, as well as one or more pharmaceutically acceptable carriers therefor, optionally known and used in the art. A pharmaceutical composition is provided that includes other therapeutic and / or prophylactic ingredients. The carrier or carriers must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.

  The pharmaceutical compositions of the present invention can be administered by any suitable route appropriate to the desired treatment. Preferred routes of administration include oral administration, particularly in tablets, capsules, dragees, powders or in liquid form, and parenteral administration, particularly in skin, subcutaneous, intramuscular or intravenous injection. The pharmaceutical compositions of the invention can be manufactured by any person skilled in the art by using standard methods and conventional techniques appropriate to the desired formulation. If desired, compositions adapted to provide sustained release of the active ingredient can be used.

  Further details on formulation and administration techniques can be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

  The actual dosage will depend on the nature and severity of the disease being treated and is within the discretion of the physician and will vary with the increase or decrease in dosage according to the particular circumstances of the invention to produce the desired therapeutic effect. Can do. However, pharmaceutical compositions containing about 0.1 to about 500 mg, preferably about 1 to about 100 mg, most preferably about 1 to about 10 mg of active ingredient per individual dose are currently suitable for therapeutic treatment Is intended to be.

  The active ingredient can be administered at one or several doses per day. In one example, 0.1 μg / kg i. v. (Intravenous) and 1 μg / kg p. o. Satisfactory results can be obtained with a low dose (oral). The upper limit of the dose range is currently about 10 mg / kg i. v. And 100 mg / kg p. o. It is thought that. A preferred range is from about 0.1 μg / kg to about 10 mg / kg / day i. v. And about 1 μg / kg to about 100 mg / kg / day p. o. It is.

Part Kit for Medicine According to the present invention, a kit of parts (kit of parts) comprising at least two separate unit dosage forms (A) and (B) for patients in need thereof:
(A) an aromatic heterocyclic carboxylic acid amide derivative of the present invention; and (B1) a phosphodiesterase inhibitor; or (B2) an agent that enhances an endothelium-derived hyperpolarizing factor-mediated response; and optionally (C) Instructions for simultaneous, sequential or separate administration of the aromatic heterocyclic carboxylic acid amide derivative A of the present invention and the phosphodiesterase inhibitor B1 or the agent B2 which enhances the response mediated by endothelium-derived hyperpolarizing factor are also provided. provide.

  In a more preferred embodiment, the phosphodiesterase inhibitor (B1) for use according to the present invention is a phosphodiesterase 5 (PDE5) inhibitor, and in a still more preferred embodiment the phosphodiesterase inhibitor for use according to the present invention is: Sildenafil, tadalafil or vardenafil.

  In another more preferred embodiment, the agent (B2) that enhances the endothelium-derived hyperpolarizing factor-mediated response used according to the present invention is calcium dobesilate.

  Aromatic heterocyclic carboxylic acid amide derivatives of the present invention, and phosphodiesterase inhibitors used according to the present invention or agents that enhance endothelium-derived hyperpolarizing factor mediated responses are suitable for administration with the other Preferably it can be provided in the form. This is intended to include examples in which one or the other of the two formulations can be administered (possibly repeated) before, after and / or simultaneously with the administration of the other component. .

  Also, the aromatic heterocyclic carboxylic acid amide derivative of the present invention and the phosphodiesterase inhibitor used according to the present invention or the agent that enhances the response mediated by endothelium-derived hyperpolarizing factor may be combined or separately. Alternatively, they can be administered separately and sequentially, in which case the sequential administrations are close in time or remote in time. This can include, in particular, the two formulations being administered in close proximity in time (possibly repeated), in the absence of the other formulation over the course of treatment of the associated medical condition. This is because the patient has a greater beneficial effect over the same course of treatment than when either of the two formulations is administered alone (sometimes repeatedly). It will depend on the medical condition to be treated or prevented, although it will depend on the medical condition to be treated or prevented, to determine whether the combination will provide a greater beneficial effect for the particular medical condition and over the course of its treatment. It can be achieved on a daily basis.

  As used in this context, the terms “administered simultaneously” and “administered at the same time as” include individual doses of positive allosteric nicotinic receptor modulators and This includes administering cognitive enhancers within 48 hours of each other, eg, 24 hours.

  Associating the two components with each other can provide components (A) and (B) as separate formulations (ie, independent of each other), which are then combined together for use together as a combination therapy Or packaging and providing together as separate components of a “combination pack” for use together with each other as a combination therapy.

Methods of Treatment In another aspect, the present invention is a method of treating, preventing or alleviating a disease, disorder or condition responsive to activation of potassium channels in the body of an animal, including a human, which requires it. There is provided a method comprising administering to such an animal's body a therapeutically effective amount of a compound capable of activating potassium channels or a pharmaceutically acceptable addition salt thereof.

  Preferred medical indications contemplated by the present invention are those listed above.

  Currently, suitable dosages of the active pharmaceutical ingredient (API) range from about 0.1 to about 1000 mg API per day, more preferably from about 1 to about 500 mg API per day, most preferably from about 1 to about 100 mg API per day. It depends on the exact method of administration, the form in which it is administered, the indication being considered, the weight of the subject concerned and in particular the subject, as well as the preference and experience of the attending physician or veterinarian. Is intended to be.

The invention is further illustrated by reference to the accompanying drawings. In the figure, for voltage dependence of BK _Ca channel expressed in Xenopus Ocytes, FIGS. 1A and 1B show compound 2 (ie 1- (4-chloro-phenyl) -5-trifluoromethyl). 1H-pyrazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide) shows the effect of compound 1 (ie 5- ( FIG. 3A and 3B show the effect of 4-chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide). Is compound 9 (ie 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid [5-chloro -2-(1H-tetrazol-5-yl) - phenyl] - it shows the effect of amide).

  The invention is further illustrated with reference to the following examples which are in no way intended to limit the scope of the claimed invention.

Example 1
Preparation Examples Abbreviations used in this specification:
AcOEt: ethyl acetate,
CFM: chloroform,
DCM: dichloromethane,
DMF: N, N-dimethylformamide,
DMAP: 4-dimethylaminopyridine,
EDC.HCl: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride,
EtOH: ethanol,
Hex: hexane,
MeOH: methanol,
MgSO4: magnesium sulfate,
PE: petroleum ether (fraction boiling at 40-60 ° C.),
Py: pyridine,
TEA: triethylamine,
THF: tetrahydrofuran,
TOL: Toluene.

Preparation of Intermediate N- (4-Chloro-2-nitro-benzoyl) -methanesulfonamide (INT-1) (Scheme 1)
To a suspension of 4-chloro-2-nitrobenzoic acid (5 g, 1 eq) in DCM (100 ml) is added EDC.HCl (9.5 g, 2 eq) and DMAP (9 g, 3 eq). The resulting brown solution is stirred for 10 minutes and then methanesulfonamide (2.35 g, 1 eq) is added. The reddish solution is stirred at room temperature overnight, diluted with DCM (100 ml), washed with 1.5N HCl (2 × 50 ml) and water (50 ml), dried and evaporated to dryness to give a yellowish solid (4 .6 g, yield 67%). This crude material was suspended in DCM (15 ml), stirred for 15 minutes, filtered and dried to give the title compound as a white solid (2 g, 29%, purity 98%), which was taken as such for the next step. We are using for.

N- (2-amino-4-chloro-benzoyl) -methanesulfonamide (INT-2) (Scheme 1)
To a solution of intermediate H (1 g, 1 eq) in MeOH (80 ml) is carefully added Raney-nickel (0.2 g). The reaction mixture is hydrogenated for 7 hours and then filtered through celite. The celite was washed with MeOH (50 ml) and the filtrate was evaporated to give the title compound as an off-white solid (0.8 g, 90% yield; 84% purity). This compound is used directly for the next step without further purification.

(5-Chloro-2-hydroxy-phenyl) -carbamic acid tert-butyl ester (INT-3) (Scheme 2)
To an ice-cold solution of commercial 2-amino-4-chlorophenol (10 g, 1 eq) in 1,4-dioxane (50 ml) was added boc-anhydride (15.96 g, 1.05 in 1,4-dioxane). Equiv.) Of ice-cold solution is added and the resulting mixture is stirred at room temperature overnight. The reaction mixture was then diluted with DCM (100 ml), washed with water (2 × 100 ml), brine (2 × 100 ml), dried over MgSO ₄ and evaporated to dryness to give a brownish gum (17.2 g), which is purified by flash column chromatography (using 230-400 mesh silica gel) and eluted with 4% AcOEt in Hex (12.1 g, 71% yield).

(5-Chloro-2-cyanomethoxy-phenyl) -carbamic acid tert-butyl ester (INT-4) (Scheme 2)
To a suspension of INT-3 (5 g, 1 eq) in 2-butanone (20 ml) was added sodium iodide (3.69 g, 1.2 eq) and potassium carbonate (3.40 g, 1.2 eq) and Chloroacetonitrile (1.86 g, 1.2 eq) is added. The reaction mixture is heated at 85 ° C. for 24 hours, then poured into water (100 ml) and extracted with AcOEt (2 × 75 ml). The combined organic phases were washed with water (100 ml), brine (100 ml), dried over MgSO ₄ and evaporated to dryness to give a brownish semi-solid (5.08 g, yield). 100%).

[5-Chloro-2- (1H-tetrazol-5-ylmethoxy) -phenyl] -carbamic acid tert-butyl ester (INT-5) (Scheme 2)
A suspension of INT-4 (0.2 g, 1 eq), sodium azide (0.092 g, 2 eq) and ammonium chloride (0.007, 2 eq) in DMF (5 ml) is heated for 6 hours ( 120 ° C). The reaction mixture is evaporated to dryness to give a brownish rubbery residue which is suspended in a mixture of water (50 ml) and 1.5N HCl (10 ml) and stirred at room temperature for 30 minutes. The resulting white solid was filtered, washed with water and dried to give the title compound (0.200 mg, 86% yield).

5-Chloro-2- (1H-tetrazol-5-ylmethoxy) -phenylamine (INT-6) (Scheme 2)
To a stirred and ice-cooled suspension of INT-5 (0.5 g, 1 eq) in DCM (30 ml) was added dropwise trifluoroacetic acid (1.19 ml, 10 eq) in DCM (10 ml). And the resulting mixture is stirred at room temperature for 2 hours. The organic solution is washed several times with water and dried over MgSO ₄ to give the title compound (0.35 g, 100% yield).

  INT-7, INT-8, INT-9 were synthesized as described by Ishikawa et al. In Journal of Medicinal Chemistry 1985 28 (10) 1387-1393.

2-Amino-4-chloro-N-hydroxy-5-morpholin-4-yl-benzamidine (INT-10) (Scheme 3)
To a stirred and boiling solution of INT-7 (0.200 g, 1 eq) in EtOH (10 ml) was added hydroxylamine hydrochloride (0.119 g, 2 eq) and sodium bicarbonate (5 ml) in water (5 ml). 0.212 g, 3 eq) solution is added and reflux is continued for 8 hours. The reaction mixture is evaporated to dryness, the residue is suspended in water (20 ml) and the resulting suspension is filtered, washed with water and dried (0.140 g, 63% yield). This compound is used as is for the next step.

2-Amino-4-chloro-5-dimethylamino-N-hydroxy-benzamidine (INT-11) (Scheme 3)
To a stirred and boiling solution of INT-8 (0.200 g, 1 eq) in EtOH (10 ml) was added hydroxylamine hydrochloride (0.145 g, 2 eq) and sodium bicarbonate (5 ml) in water (5 ml). 0.257 g, 3 eq) solution is added and reflux is continued for 8 hours. The reaction mixture is evaporated to dryness, the residue is suspended in water (20 ml) and the resulting suspension is filtered, washed with water and dried (0.150 g, 67% yield). This compound is used as is for the next step.

2-Amino-4-chloro-N-hydroxy-5-piperidin-1-yl-benzamidine (INT-12) (Scheme 3)
To a stirred and boiling solution of INT-9 (0.200 g, 1 eq) in EtOH (10 ml) was added hydroxylamine hydrochloride (0.120 g, 2 eq) and sodium bicarbonate (5 ml) in water (5 ml). 0.214 g, 3 eq) solution is added and reflux is continued for 8 hours. The reaction mixture is evaporated to dryness, the residue is suspended in water (20 ml) and the resulting suspension is filtered, washed with water and dried (0.190 g, 86% yield). This compound is used as is for the next step.

3- (2-Amino-4-chloro-5-morpholin-4-yl-phenyl) -4H- [1,2,4] oxadiazol-5-one (INT-13) (Scheme 3)
To a stirred and boiling solution of sodium (0.0256 g, 2 eq) in absolute EtOH (10 ml), INT-10 (0.150 g, 1 eq) is added and reflux is continued for 1 hour. Then 0.27 ml (4 equivalents) of diethyl carbonate is added and reflux is continued for 24 hours. The reaction mixture is evaporated to dryness and the residue is suspended in 0.5M HCl (5 ml). The suspension is stirred overnight and filtered to give the title compound as a white powder (0.120 g, 73% yield), which is used as such for the next step.

3- (2-Amino-4-chloro-5-dimethylamino-phenyl) -4H- [1,2,4] oxadiazol-5-one (INT-14) (Scheme 3)
To a stirred and boiling solution of sodium (0.0202 g, 2 eq) in absolute EtOH (10 ml), INT-11 (0.100 g, 1 eq) is added and reflux is continued for 1 hour. Then 0.214 ml (4 equivalents) of diethyl carbonate are added and reflux is continued for 24 hours. The reaction mixture is evaporated to dryness and the residue is suspended in 0.5M HCl (5 ml). The suspension is stirred overnight and filtered to give the title compound as a white powder (0.072 g, 63% yield), which is used as such for the next step.

スキーム２

スキーム３

3- (2-Amino-4-chloro-5-piperidin-1-yl-phenyl) -4H- [1,2,4] oxadiazol-5-one (INT-15) (Scheme 3)
To a stirred and boiling solution of sodium (0.507 g, 2 eq) in absolute EtOH (30 ml), INT-11 (2.95 g, 1 eq) is added and reflux is continued for 1 h. 5.37 ml (4 equivalents) of diethyl carbonate are then added and reflux is continued for 24 hours. The reaction mixture is evaporated to dryness and the residue is suspended in 0.5M HCl (25 ml). The suspension is stirred overnight and filtered to give the title compound as a white powder (0.072 g, 63% yield), which is used as such for the next step. Melting point: 186.3-189.4 ° C.
Scheme 1

Scheme 2

Scheme 3

5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide (1)
To a solution of commercial 5- (4-chlorophenyl) -2- (trifluoromethyl) furan-3-carbonyl chloride (0.2 g, 1 eq) in dry THF (6 ml) under nitrogen was added TEA (0.45 ml). 5 eq) and 5-chloro-2 (1H-tetrazol-5-yl) -phenylamine (0.150 g, 1 eq) (described by Valgeirsson et al. In Journal of Medicinal Chemistry 2004 47 (27) 6948-6957). As prepared). The mixture is kept stirring overnight under nitrogen and at room temperature and then poured into water (20 ml). The resulting suspension is extracted with ethyl acetate (3 × 25 ml) and the combined organic phases are washed with 1.5N HCl, water, dried over MgSO 4 and evaporated to dryness. A yellow solid (0.32 g) is obtained. The crude material is purified by flash column chromatography (using 230-400 mesh silica gel) eluting with 8% MeOH in CFM to give the title compound as a white powder (0.105 g, 32% yield). . LC-ESI-HRMS of [M-H]-shows 466.0078 Da. Calculated 466.00854 Da, deviation -1.6 ppm.

1- (4-Chloro-phenyl) -5-trifluoromethyl-1H-pyrazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide (2)
To a suspension of commercial 2- (4-chlorophenyl) -3- (trifluoromethyl) -pyrazole-4-carboxylic acid (0.235 g, 1 eq) in DCM (10 ml) was added EDC.HCl (0.31 g 2 equivalents) and DMAP (0.30 g, 3 equivalents). The resulting mixture was stirred at room temperature for 10 minutes and 5-chloro-2- (1H-tetrazol-5-yl) -phenylamine (0.144 g, 1 eq) (Journal of Medicinal Chemistry 2004 47 (27) 6948- (Prepared as described by Valgeirson et al. In 6957) and stirring is continued overnight at room temperature. The reaction mixture is diluted with DCM (20 ml), washed with 1.5N HCl (2 × 15 ml) and water (15 ml), dried and evaporated to dryness to give a yellow solid (0.255 g). The crude material was purified by flash column chromatography using silica gel (230-400 mesh) eluting with 0-5% MeOH in CFM to give the title compound as a white powder (0. 0. 090 g, yield 24%). LC-ESI-HRMS with a melting point of 176.3-180.4 [deg.] C. [MH]-shows 466.0193 Da. Calculated value 466.0019773 Da, deviation -1 ppm.

1- (4-Bromo-benzyl) -5-methyl-1H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide (3)
Stirring suspension of commercially available 1- (4-bromo-benzyl) -5-methyl-1H- [1,2,3] triazole-4-carboxylic acid (0.200 g, 1 eq) in DCM (15 ml). To the suspension, excess oxalyl chloride (1 ml) is added dropwise at 0 ° C. followed by 1-2 drops of dry DMF. The resulting yellow solution is allowed to naturally reach room temperature and is then stirred on TLC at room temperature until the starting material has completely disappeared (˜1 hour). The mixture is then evaporated to dryness under vacuum and the residue is dissolved in DCM and washed with cold aqueous NaHCO ₃ solution. The organic phase, dried over MgSO ₄ and evaporated to dryness, was 0.212 g (˜100% yield) of 1- (4-bromo-benzyl) -5-methyl-1H- [1,2,3] triazole. 4-Carbonyl chloride is provided, which is dissolved in TOL (10 ml) and Py (0.5 ml) under nitrogen. The new solution was ice-cooled and in 5-chloro-2- (1H-tetrazol-5-yl) -phenylamine (0.119 g, 0.9 eq) (Journal of Medicinal Chemistry 2004 47 (27) 6948-6957. (Prepared as described by Valgeirsson et al.) And continue to stir overnight at room temperature under nitrogen. The reaction mixture is evaporated to dryness and the crude solid residue is purified by crystallization from MeOH (0.105 g, 22% yield). LC-ESI-HRMS of [M-H]-shows 471.007 Da. Calculated value 471.008423 Da, deviation -3 ppm.

5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid (5-chloro-2-phenyl-carbamoyl-phenyl) -amide (4)
To a suspension of commercially available 5- (4-chlorophenyl) -2- (trifluoromethyl) furan-3-carboxylic acid (0.25 g, 1 eq) in DCM (10 ml) was added EDC.HCl (0.33 g, 2 equivalents) and DMAP (0.315 g, 3 equivalents). The resulting brown solution is stirred for 10 minutes and then commercially available 2-amino-4-chloro-N-phenyl-benzamide (0.21 g, 1 eq) is added. The reaction mixture was stirred at room temperature overnight, diluted with DCM (20 ml), washed with 1.5N HCl (2 × 25 ml) and water (25 ml), finally dried over MgSO ₄ and evaporated to dryness. To give a yellowish solid (0.315 g). The crude material was purified by flash chromatography using silica gel (230-400 mesh) eluting with 0-10% AcOEt in Hex to give the title compound as a white powder (0.120 g Yield 27%). Melting point: 176.3-180.4 ° C.

5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid (5-chloro-2-methanesulfonylaminocarbonyl-phenyl) -amide (5)
To an ice-cold solution of commercial 5- (4-chlorophenyl) -2- (trifluoromethyl) furan-3-carbonyl chloride (0.200 g, 1 eq) in dry THF (10 ml) under nitrogen, Py (0 .1 ml, 2 eq) and INT-2 (0.161 g, 1 eq) are added. The mixture is kept stirring overnight under nitrogen and at room temperature and then poured into water (20 ml). The resulting suspension is extracted with ethyl acetate (3 × 25 ml) and the combined organic phases are washed with 1.5N HCl, water, dried over MgSO ₄ and evaporated to dryness. To obtain a yellow solid (0.200 g). The crude material was purified by flash column chromatography (using 60-120 mesh silica gel) eluting with 5% MeOH in CFM to give the title compound as a white powder (0.055 g, yield 16). %). Melting point: 259-262 ° C. LC-ESI-HRMS of [M + H] + shows 520.9935 Da. Calculated value 520.9995259 Da, deviation -3.4 ppm.

4-chloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzenesulfonic acid (6)
To a suspension of commercial 5- (4-chlorophenyl) -2- (trifluoromethyl) furan-3-carboxylic acid (0.27 g, 1 eq) in DCM (15 ml) was added EDC.HCl (0.214 g, 2 equivalents) and DMAP (0.227 g, 2 equivalents). The resulting brown solution was stirred for 10 minutes, and then commercially available 2-amino-4-chloro-benzenesulfonic acid (0.202 g, 1 Eq.) Is added. The reaction mixture was stirred at room temperature overnight, diluted with DCM (20 ml), washed with 1.5N HCl (2 × 25 ml) and water (25 ml), finally dried over MgSO ₄ and evaporated to dryness. To give a yellowish solid (0.300 g). This crude material was purified by preparative HPLC (0.070 g, 16% yield) to yield the title compound as a white powder. LC-ESI-HRMS of [M + H] + shows 479.9855 Da. Calculated value 479.968871 Da, deviation -0.4 ppm.

5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (1H-tetrazol-5-ylmethoxy) -phenyl] -amide (7)
To an ice-cold solution of commercial 5- (4-chlorophenyl) -2- (trifluoromethyl) furan-3-carbonyl chloride (0.500 g, 1 eq) in dry DCM (25 ml) under nitrogen was added TEA (0 .64 ml, 3 eq) and INT-6 (0.346 g, 1 eq) are added. The mixture was kept stirring overnight at room temperature under nitrogen and then evaporated to dryness to give an off-white solid (˜0.700 g). The crude residue was purified by flash chromatography on neutral alumina, eluting with 20% MeOH in CFM to give the title compound as a white powder (0.423 g, 55% yield). Melting point: 226.9-236, 1 ° C. LC-ESI-HRMS of [M + H] + shows 498.0331 Da. Calculated value 498.034755 Da, deviation -3.3 ppm.

4,5-dichloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzenesulfonic acid (8)
To an ice-cold solution of commercial 5- (4-chlorophenyl) -2- (trifluoromethyl) furan-3-carbonyl chloride (0.250 g, 1 eq) in dry DCM (15 ml) under nitrogen, Py (0 2 ml, 3 eq) and 2-amino-4,5-dichloro-benzenesulfonic acid (0.125 g, 1 eq) (prepared as described in DE 4112692) are added. The mixture is kept stirring overnight at room temperature under nitrogen and then diluted with DCM (20 ml). The new solution, 1.5N HCl (2 × 25ml) , washed with water (2 × 25), dried over MgSO _4, evaporated to dryness, to give a yellow solid (0.372 g). The crude material was purified by flash column chromatography (using 230-400 mesh silica gel) eluting with 3% MeOH in CFM to give the title compound as a white powder (0.145 g, yield). 38%). LC-ESI-HRMS of [M + H] + shows 513.9299 Da. Calculated value 513.992938 Da, deviation 0.3 ppm.

4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide (9)
To a solution of commercially available 4-methyl-2- [4- (trifluoromethyl) phenyl] -1,3-thiazole-5-carbonyl chloride (0.300 g, 1 eq) in dry THF (7 ml) under nitrogen. , TEA (0.27 ml, 2 equivalents) and 5-chloro-2 (1H-tetrazol-5-yl) -phenylamine (0.194 g, 1 equivalent) (Journal of Medicinal Chemistry 2004 47 (27) 6948-6957. (Prepared as described by Valgeirsson et al.). The mixture is kept stirring overnight under nitrogen and at room temperature and then poured into water (40 ml). The resulting suspension is extracted with ethyl acetate (3 × 40 ml) and the combined organic phases are washed with 1.5N HCl, water, dried over MgSO 4 and evaporated to dryness. A brown solid (0.325 g) is obtained. The crude material was purified by flash column chromatography (using 230-400 mesh silica gel) eluting with 2% MeOH in CFM to give the title compound as a white powder (0.124 g, 27 yield). %). Mp 325-337.2 ° C. LC-ESI-HRMS of [M + H] + shows 465.0503 Da. Calculated value 465.051217 Da, deviation -2 ppm.

4-chloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzoic acid (10)
To a solution of commercial 5- (4-chlorophenyl) -2- (trifluoromethyl) furan-3-carbonyl chloride (0.200 g, 1 eq) in dry DCM (10 ml) under nitrogen, Py (0.13 ml). 3 equivalents) and commercially available 2-amino-4-chlorobenzoic acid (0.111, 1 equivalent). The mixture is kept stirring overnight under nitrogen and at room temperature. The resulting mixture is quenched with 1.5N HCl (20 ml) and then extracted with DCM (3 × 25 ml). The combined organic phases were dried over MgSO4 and evaporated to dryness to give a yellow solid (0.279 g). The crude material was purified by flash column chromatography (using 60-120 mesh silica gel), eluting with 3% MeOH in CFM to give the title compound as a white powder (0.191 g, 66 yield). %). LC-ESI-HRMS of [M-H]-shows 441.9844 Da. Calculated value 441.998674 Da, deviation -3.8 ppm.

4-chloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzoylcyanamide (11)
To an ice-cooled and stirring suspension of sodium hydride (0.027 g, 2 eq) in dry THF (5 ml), cyanamide (0.014 g, 1 eq) was added and stirred at room temperature for 30 min. continue. Meanwhile, when compound 10 is treated with oxalyl chloride, the corresponding acid chloride (4-chloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl]- Amino} -benzoyl chloride). A solution of this latter (1 eq) in THF (15 ml) is added dropwise to an ice-cold mixture of sodium cyanamide in THF and stirring is continued for 1 hour at room temperature. The reaction mixture is then quenched with 10 ml of water and extracted with AcOEt (3 × 30 ml). The organic phase was washed with water, dried over MgSO4 and evaporated to dryness to give a brownish solid (0.02 g) which was purified by flash column chromatography (using 60-120 mesh silica gel), Elution with 8% MeOH in CFM gives the title compound as a white powder (0.045 g, 25% yield). LC-ESI-HRMS of [M + H] + shows 468.0115 Da. Calculated value 468.012957 Da, deviation -3.1 ppm.

5- (4-Chloro-phenyl) -2-methyl-furan-3-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide (12)
To a solution of commercially available 5- (4-chlorophenyl) -2-methylfuran-3-carbonyl chloride (0.100 g, 1 eq) in dry THF (10 ml) under nitrogen, TEA (0.08 ml, 1.5 Eq) and 5-chloro-2- (1H-tetrazol-5-yl) -phenylamine (0.078 g, 1 eq) (as described by Valgeirsson et al. In Journal of Medicinal Chemistry 2004 47 (27) 6948-6957). (Prepared). The mixture is kept stirring overnight under nitrogen and at room temperature. The resulting mixture is quenched with 1.5N HCl (10 ml) and then extracted with AcOEt (3 × 25 ml). The combined organic phases were dried over MgSO 4 and evaporated to dryness to give a white solid (0.135 g). The crude material was purified by crystallization from AcOEt / PE to yield the title compound as an off-white solid (0.042 g, 26% yield). Melting point 246.7-255.4 [deg.] C. LC-ESI-HRMS of [M + H] + shows 414.0537 Da. Calculated value 414.052456 Da, deviation 3 ppm.

2-{[5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -4,5-difluoro-benzoic acid (13)
To a solution of commercially available 5- (4-chlorophenyl) -2- (trifluoromethyl) furan-3-carbonyl chloride (0.100 g, 1 eq) in dry THF (15 ml) under nitrogen, TEA (0.18 ml 4 equivalents) and commercially available 2-amino-4,5-difluorobenzoic acid (0.056, 1 equivalent). The mixture is kept stirring overnight under nitrogen and at room temperature. The resulting mixture is quenched with 1.5N HCl (10 ml) and then extracted with AcOEt (3 × 25 ml). The combined organic phases were dried over MgSO4 and evaporated to dryness to give a white solid (0.122 g). The crude material was purified by flash column chromatography (using 60-120 mesh silica gel), eluting with 3% MeOH in CFM to give the title compound as a white powder (0.060 g, yield 42). %). Melting point 337.2-340.2 [deg.] C. LC-ESI-HRMS of [M-H]-shows 444.0058 Da. Calculated value 444.006202 Da, deviation -0.9 ppm.

4,5-Dichloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzenesulfonic acid methyl ester (14)
To an ice-cold suspension of 8 (0.070 g) in dry DCM (2 ml) was added methyl trifluoromethanesulfonate (0.025 g, 1.1 eq) and TEA (0.021 ml, 1.1 eq). And the resulting mixture is stirred at room temperature overnight. Evaporation to dryness yielded ˜70 mg of crude solid material that was purified by flash chromatography on neutral alumina and eluting with 4% AcOEt in PE (0.018 g, 25% yield). %). LC-ESI-HRMS of [M-H]-shows 525.9299 Da. Calculated value 525.992938 Da, deviation 0.3 ppm.

5-Methyl-2-phenyl-2H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide (15)
To a suspension of 4-methyl-2-phenyl-1,2,3-triazole-5-carboxylic acid (0.25 g, 1 equivalent) in DCM (15 ml) was added EDC.HCl (0.472 g, 2 equivalents). ) And DMAP (0.451 g, 3 eq). The resulting brown solution was stirred for 10 minutes and 5-chloro-2- (1H-tetrazol-5-yl) -phenylamine (0.241 g, 1 equivalent) (Journal of Medicinal Chemistry 2004 47 (27) 6948-6957. Prepared as described by Valgeirsson et al. The solution was stirred at room temperature overnight, diluted with DCM (20 ml), washed with 1.5N HCl (30 ml) and water (30 ml), dried, evaporated to dryness and a yellowish solid (0.369 g ). The crude material is purified by crystallization from DCM (0.250, 53% yield). LC-ESI-HRMS of [M + H] + shows 381.099 Da. Calculated value 381.09791 Da, deviation 2.9 ppm.

5-trifluoromethyl-2- (4-trifluoromethyl-phenyl) -oxazole-4-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxa Diazol-3-yl) -phenyl] -amide (16)
To a suspension of 5- (trifluoromethyl) -2- [4- (trifluoromethyl) phenyl] -1,3-oxazole-4-carboxylic acid (0.25 g, 1 eq) in DCM (15 ml). , EDC.HCl (0.295 g, 2 eq) and DMAP (0.282 g, 3 eq). The resulting solution was stirred for 10 minutes and 3- (2-amino-4-chloro-phenyl) -4H- [1,2,4] oxadiazol-5-one (0.166 g, 1 equivalent) (Journal). of Medicinal Chemistry 2004 47 (27) 6948-6957, prepared as described by Valgeirsson et al.). The solution is stirred overnight at room temperature, diluted with DCM (20 ml), washed with 1.5N HCl (30 ml) and water (30 ml), dried and evaporated to dryness to give a pure white solid. (0.176 g, 45% yield). LC-ESI-HRMS of [M-H]-shows 517.0135 Da. Calculated value 517.013827 Da, deviation -0.6 ppm.

5-Trifluoromethyl-2- (4-trifluoromethyl-phenyl) -oxazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide (17)
To a suspension of 5- (trifluoromethyl) -2- [4- (trifluoromethyl) phenyl] -1,3-oxazole-4-carboxylic acid (0.25 g, 1 eq) in DCM (15 ml). , EDC.HCl (0.295 g, 2 eq) and DMAP (0.282 g, 3 eq). The resulting solution was stirred for 10 min and in 5-chloro-2- (1H-tetrazol-5-yl) -phenylamine (0.150 g, 1 eq) (Journal of Medicinal Chemistry 2004 47 (27) 6948-6957 (Prepared as described by Valgeirsson et al.). The solution was stirred overnight at room temperature, diluted with DCM (20 ml), washed with 1.5N HCl (30 ml) and water (30 ml), dried and evaporated to dryness to give a solid residue (0.340 g) Which is purified by crystallization from EtOH (0.142 g, 37%). LC-ESI-HRMS of [M-H]-shows 501.0297 Da. Calculated value 501.030145 Da, deviation -0.9 ppm.

5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole) -3-yl) -phenyl] -amide (18)
To a solution of commercial 5- (4-chlorophenyl) -2- (trifluoromethyl) furan-3-carbonyl chloride (0.2 g, 1 eq) in dry THF (6 ml) under nitrogen was added TEA (0.45 ml). 5 eq) and 3- (2-amino-4-chloro-phenyl) -4H- [1,2,4] oxadiazol-5-one (0.160 g, 1 eq) (Journal of Medicinal Chemistry 2004 47 (27) prepared as described by Valgeirson et al. In 6948-6957). The mixture is kept stirring overnight under nitrogen and at room temperature and then poured into water (20 ml). The resulting suspension is extracted with ethyl acetate (3 × 25 ml) and the combined organic phases are washed with 1.5N HCl, water, dried over MgSO 4 and evaporated to dryness. A yellow solid (0.301 g) was obtained. The crude material was purified by flash column chromatography (using 230-400 mesh silica gel) eluting with 20% AcOEt in Hex to give the title compound as a white powder (0.145 g, 36% yield). %). LC-ESI-HRMS of [M + H] + shows 484.0063 Da. Calculated 484.007872 Da, Deviation -3.2 ppm.

5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [4,5-dichloro-2- (1H-tetrazol-5-yl) -phenyl] -amide (19)
To a solution of commercial 5- (4-chlorophenyl) -2- (trifluoromethyl) furan-3-carbonyl chloride (0.1 g, 1 eq) in dry DCM (6 ml) under nitrogen was added TEA (0.225 ml). 5 equivalents) and 4,5-dichloro-2- (1H-tetrazol-5-yl) -phenylamine (0.074, 1 equivalent) as described, for example, in US Pat. No. 3,838,126. The resulting mixture is quenched with 1.5N HCl (10 ml) and then extracted with DCM (3 × 20 ml). The combined organic phases were dried over MgSO4 and evaporated to dryness to give a yellow solid (0.160 g). The crude material was purified by flash column chromatography (using 60-120 mesh silica gel) eluting with 5% MeOH in CFM to give the title compound as a white powder (0.030 g, yield 18 %). LC-ESI-HRMS of [M-H]-shows 499.9698 Da. Calculated value 499.969568 Da, deviation 0.5 ppm.

5- (4-Chloro-phenyl) -2-methyl-furan-3-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole-3 -Yl) -phenyl] -amide (20)
To a solution of commercial 5- (4-chlorophenyl) -2-methylfuran-3-carbonyl chloride (0.100 g, 1 equivalent) in dry THF (7 ml) under nitrogen, TEA (˜0.3 ml, 5 equivalents). ) And 3- (2-amino-4-chloro-phenyl) -4H- [1,2,4] oxadiazol-5-one (0.1167, 1.2 eq) (Journal of Medicinal Chemistry 2004 47 ( 27) (prepared as described by Valgeirsson et al. In 6948-6957). The resulting mixture is quenched with 1.5N HCl (10 ml) and then extracted with DCM (3 × 20 ml). The combined organic phases were dried over MgSO4 and evaporated to dryness to give a yellow solid (0.150 g). The crude material was purified by flash column chromatography (using 230-400 mesh silica gel) eluting with 2% MeOH in CFM to give the title compound as a white powder (0.055 g, yield 25). %). LC-ESI-HRMS of [M-H]-shows 428.00211 Da. Calculated value 428.0020488 Da, deviation 1.4 ppm. Melting point: 248.1-250.9 ° C.

2- (4-Chloro-benzyl) -thiazole-4-carboxylic acid [5-chloro-2- (5-oxo-2,5-dihydro- [1,2,4] oxadiazol-3-yl)- Phenyl] -amide (21)
To a suspension of commercial 2- (4-chloro-benzyl) -thiazole-4-carboxylic acid (0.25 g, 1 eq) in DCM (10 ml) was added EDC.HCl (0.3778 g, 2 eq) and DMAP. (0.3612 g, 3 eq) is added. The resulting solution was stirred for 10 minutes and 3- (2-amino-4-chloro-phenyl) -4H- [1,2,4] oxadiazol-5-one (0.2085 g, 1 equivalent) (Journal). of Medicinal Chemistry 2004 47 (27) 6948-6957, prepared as described by Valgeirsson et al.). The solution was stirred overnight at room temperature, diluted with DCM (20 ml), washed with 1.5N HCl (30 ml) and water (30 ml), dried and evaporated to dryness to give a solid residue (0.400 g Which was purified by preparative LCMS to give the title compound as a white powder (0.088 g, 20% yield). LC-ESI-HRMS of [M + H] + shows 447.008 Da. Calculated 447.008543 Da, deviation -1.2 ppm.

1- (4-Bromo-benzyl) -5-methyl-1H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1, 2,4] oxadiazol-3-yl) -phenyl] -amide (22)
To a suspension of commercially available 1- (4-bromo-benzyl) -5-methyl-1H- [1,2,3] triazole-4-carboxylic acid (0.25 g, 1 equivalent) in DCM (10 ml). Add EDC.HCl (0.3237 g, 2 eq) and DMAP (0.3094 g, 3 eq). The resulting solution was stirred for 10 minutes and 3- (2-amino-4-chloro-phenyl) -4H- [1,2,4] oxadiazol-5-one (0.1786 g, 1 equivalent) (Journal). of Medicinal Chemistry 2004 47 (27) 6948-6957, prepared as described by Valgeirsson et al.). The solution was stirred at room temperature overnight, diluted with DCM (20 ml), washed with 1.5N HCl (30 ml) and water (30 ml), dried and evaporated to dryness to give a solid residue (˜0. Which was purified by crystallization from DMSO / water to give the title compound as a white powder (˜0.080 g, yield˜20%). LC-ESI-HRMS of [M + H] + shows 489.0091 Da. Calculated value 489.0007755 Da, deviation 2.8 ppm.

4-Methyl-2-morpholin-4-yl-thiazole-5-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl) ) -Phenyl] -amide (23)
To a suspension of commercial 4-methyl-2-morpholin-4-yl-thiazole-5-carboxylic acid (0.25 g, 1 eq) in DCM (10 ml), EDC.HCl (0.4538 g, 2 eq) And DMAP (0.4338 g, 3 eq) are added. The resulting solution was stirred for 10 minutes and 3- (2-amino-4-chloro-phenyl) -4H- [1,2,4] oxadiazol-5-one (0.250 g, 1 equivalent) (Journal). of Medicinal Chemistry 2004 47 (27) 6948-6957, prepared as described by Valgeirsson et al.). The solution was stirred at room temperature overnight, diluted with DCM (20 ml), washed with 1.5N HCl (30 ml) and water (30 ml), dried and evaporated to dryness to give a solid residue (˜0. 370 g) which was purified by crystallization from DMSO / water to give the title compound as a white powder (0.126 g, yield ˜20%). LC-ESI-HRMS of [M + H] + shows 422.0686 Da. Calculated value 422.068797 Da, deviation -0.9 ppm.

4-Methyl-2-morpholin-4-yl-thiazole-5-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide (24)
To a suspension of commercial 4-methyl-2-morpholin-4-yl-thiazole-5-carboxylic acid (0.25 g, 1 eq) in DCM (10 ml), EDC.HCl (0.4538 g, 2 eq) And DMAP (0.4338 g, 3 eq) are added. The resulting solution was stirred for 10 minutes and in 5-chloro-2- (1H-tetrazol-5-yl) -phenylamine (0.2315 g, 1 equivalent) (Journal of Medicinal Chemistry 2004 47 (27) 6948-6957. (Prepared as described by Valgeirsson et al.). The solution was stirred at room temperature overnight, diluted with DCM (20 ml), washed with 1.5N HCl (30 ml) and water (30 ml), dried and evaporated to dryness to give a solid residue (˜0. 390 g) which was purified by crystallization from DMSO / water to give the title compound as a white powder (0.240 g, yield ˜50%). LC-ESI-HRMS of [M + H] + shows 406.0843 Da. Calculated value 406.085297 Da, deviation -2.5 ppm.

2- (3-Chloro-phenyl) -5-methyl-2H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1, 2,4] oxadiazol-3-yl) -phenyl] -amide (25)
To a suspension of commercially available 2- (3-chloro-phenyl) -5-methyl-2H- [1,2,3] triazole-4-carboxylic acid (0.25 g, 1 eq) in DCM (10 ml), Add EDC.HCl (0.4033 g, 2 eq) and DMAP (0.3856 g, 3 eq). The resulting solution was stirred for 10 minutes and 3- (2-amino-4-chloro-phenyl) -4H- [1,2,4] oxadiazol-5-one (0.2226 g, 1 equivalent) (Journal). of Medicinal Chemistry 2004 47 (27) 6948-6957, prepared as described by Valgeirsson et al.). The solution was stirred at room temperature overnight, diluted with DCM (20 ml), washed with 1.5N HCl (30 ml) and water (30 ml), dried, evaporated to dryness and a solid residue (˜0. 400 g) which was purified by crystallization from methanol to give the title compound as a white powder (0.302 g, yield ˜67%). LC-ESI-HRMS of [M-H]-shows 429.0278 Da. Calculated value 429.002697 Da, deviation 1.9 ppm.

4- {5- [5-Chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl) -phenylcarbamoyl] -4-methyl-thiazole-2 -Yl} -piperidine-1-carboxylic acid tert-butyl ester (26)
To a suspension of commercially available 4- (5-carboxy-4-methyl-thiazol-2-yl) -piperidine-1-carboxylic acid tert-butyl ester (0.25 g, 1 eq) in DCM (10 ml) was added EDC. Add HCl (0.2937 g, 2 eq) and DMAP (0.2807 g, 3 eq). The resulting solution was stirred for 10 minutes and 3- (2-amino-4-chloro-phenyl) -4H- [1,2,4] oxadiazol-5-one (0.1621 g, 1 equivalent) (Journal). of Medicinal Chemistry 2004 47 (27) 6948-6957, prepared as described by Valgeirsson et al.). The solution was stirred at room temperature overnight, diluted with DCM (20 ml), washed with 1.5N HCl (30 ml) and water (30 ml), dried, evaporated to dryness and a solid residue (˜0. 370 g) which was purified by preparative LCMS to give the title compound as a white powder (0.101 g, yield ˜25%). LC-ESI-HRMS of [M + H] + shows 520.1411 Da. Calculated value 520.142144 Da, deviation -2 ppm.

4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole) -3-yl) -phenyl] -amide (27)
To a suspension of commercial 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid (1.00 g, 1 eq) in DCM (40 ml) was added EDC.HCl (0.8008 g). 1.2 equivalents) and DMAP (0.25104 g, 1.2 equivalents). The resulting solution was stirred for 10 minutes and 3- (2-amino-4-chloro-phenyl) -4H- [1,2,4] oxadiazol-5-one (0.7366 g, 1 equivalent) (Journal). of Medicinal Chemistry 2004 47 (27) 6948-6957, prepared as described by Valgeirsson et al.). The solution was stirred overnight at room temperature, diluted with DCM (80 ml), washed with 1.5 N HCl (120 ml) and water (120 ml), dried and evaporated to dryness to give a solid residue (˜1. Which was purified by flash column chromatography eluting with 10% MeOH in DCM to give the title compound as a white powder (0.326 g, ˜20% yield). LC-ESI-HRMS of [M + H] + shows 481.0338 Da. Calculated value 481.034899 Da, deviation -2.3 ppm.

5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-4-morpholin-4-yl-2- (5-oxo-4,5-dihydro- [1 , 2,4] oxadiazol-3-yl) -phenyl] -amide (28)
To an ice-cold solution of commercial 5- (4-chloro-phenyl) -2- (trifluoromethyl) furan-3-carbonyl chloride (0.500 g, 1 eq) in dry DCM (25 ml) under nitrogen is added TEA. (0.67 ml, 3 eq) and INT-13 (0.48 g, 1 eq) are added. The mixture was kept stirring overnight at room temperature under nitrogen and then evaporated to dryness to give an off-white solid (˜0.800 g). The crude residue was purified by flash chromatography eluting with 10% AcOEt in Hex to give the title compound as a white powder (0.131 g, 14% yield). Melting point 226.9-236.1 [deg.] C. LC-ESI-HRMS of [M + H] + shows 569.0627 Da. Calculated value 569.0060636 Da, deviation 3.6 ppm. Mp 229-234 ° C.

5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-4-dimethyl-amino-2- (5-oxo-4,5-dihydro- [1,2 , 4] oxadiazol-3-yl) -phenyl] -amide (29)
To an ice-cold solution of commercial 5- (4-chloro-phenyl) -2- (trifluoromethyl) furan-3-carbonyl chloride (0.500 g, 1 eq) in dry DCM (25 ml) under nitrogen is added TEA. (0.67 ml, 3 eq) and INT-14 (0.412 g, 1 eq) are added. The mixture was kept stirring overnight at room temperature under nitrogen and then evaporated to dryness to give an off-white solid (˜0.600 g). The crude residue was purified by flash chromatography eluting with 10% AcOEt in Hex to give the title compound as a white powder (0.32 g, 37% yield). Melting point 256.2-258.4 [deg.] C. LC-ESI-HRMS of [M + H] + shows 527.0529 Da. Calculated value 527.050071 Da, deviation 5.4 ppm.

5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole) -3-yl) -4-piperidin-1-yl-phenyl] -amide (30)
To an ice-cold solution of commercial 5- (4-chlorophenyl) -2- (trifluoromethyl) furan-3-carbonyl chloride (0.400 g, 1 eq) in dry DCM (25 ml) under nitrogen was added TEA (0 .54 ml, 3 eq) and INT-15 (0.381 g, 1 eq) are added. The mixture is kept stirring overnight at room temperature under nitrogen and then evaporated to dryness to give an off-white solid (˜0.550 g). The crude residue was purified by flash chromatography eluting with 10% AcOEt in Hex to give the title compound as a white powder (0.312 g, 43% yield). Melting point: 247.8-249.6 ° C. LC-ESI-HRMS of [M + H] + shows 567.0822 Da. Calculated value 567.081371 Da, deviation 1.5 ppm.

2- (3-Chloro-phenyl) -5-methyl-2H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl-phenyl] -amide ( 31)
To a suspension of commercially available 2- (3-chloro-phenyl) -5-methyl-2H- [1,2,3] triazole-4-carboxylic acid (0.25 g, 1 eq) in DCM (10 ml), Add EDC.HCl (0.4033 g, 2 eq) and DMAP (0.3856 g, 3 eq). The resulting solution was stirred for 10 min and in 5-chloro-2- (1H-tetrazol-5-yl) -phenylamine (0.2058 g, 1 eq) (Journal of Medicinal Chemistry 2004 47 (27) 6948-6957. (Prepared as described by Valgeirsson et al.). The solution was stirred at room temperature overnight, diluted with DCM (20 ml), washed with 1.5N HCl (30 ml) and water (30 ml), dried, evaporated to dryness and a solid residue (˜0. 400 g) which was purified by crystallization from methanol to give the title compound as a white powder (0.190 g, yield ˜43%). LC-ESI-HRMS of [M + H] + shows 415.0593 Da. Calculated value 415.05898938Da, deviation 0.9ppm.

4-Methyl-2-pyridin-4-yl-thiazole-5-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide (32)
To a suspension of commercial 4-methyl-2-pyridin-4-yl-thiazole-5-carboxylic acid (0.25 g, 1 eq) in DCM (10 ml), EDC.HCl (0.4352 g, 2 eq) And DMAP (0.416 g, 3 eq) are added. The resulting solution was stirred for 10 min and in 5-chloro-2- (1H-tetrazol-5-yl) -phenylamine (0.2058 g, 1 eq) (Journal of Medicinal Chemistry 2004 47 (27) 6948-6957. (Prepared as described by Valgeirsson et al.). The solution was stirred at room temperature overnight, diluted with DCM (20 ml), washed with 1.5N HCl (30 ml) and water (30 ml), dried and evaporated to dryness to give a solid residue (˜0. 410 g), which was purified by crystallization from methanol to give the title compound as a white powder (0.214 g, yield ˜47%). LC-ESI-HRMS of [M + H] + shows 398.0612 Da. Calculated value 398.059082 Da, deviation 5.3 ppm.

4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole) -3-yl) -4-piperidin-1-yl-phenyl] -amide (33)
To a suspension of commercially available 4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid (0.500 g, 1 eq) in DCM (25 ml) was added EDC.HCl (0.667 g 2 equivalents) and DMAP (0.638 g, 3 equivalents). The resulting solution is stirred for 10 minutes and INT-15 (0.513 g, 1 eq) is added. The solution was stirred overnight at room temperature, diluted with DCM (30 ml), washed with 1.5N HCl (45 ml) and water (45 ml), dried and evaporated to dryness to give a solid residue (0.720 g This is purified by crystallization from DMF / water (0.464 g, 47% yield). LC-ESI-HRMS of [M + H] + shows 564.1078 Da. Calculated value 564.108398 Da, deviation -1.1 ppm.

5- (Cyclopentanecarbonyl-amino) -3-methyl-thiophene-2-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide (34)
To a suspension of commercial 5- (cyclopentanecarbonyl-amino) -3-methyl-thiophene-2-carboxylic acid (0.500 g, 1 eq) in DCM (25 ml) was added EDC.HCl (0.454 g, 1 .2 equivalents) and DMAP (0.2894 g, 1.2 equivalents). The resulting solution was stirred for 10 min and in 5-chloro-2- (1H-tetrazol-5-yl) -phenylamine (0.386 g, 1 eq) (Journal of Medicinal Chemistry 2004 47 (27) 6948-6957). (Prepared as described by Valgeirsson et al.). The solution was stirred overnight at room temperature, diluted with DCM (30 ml), washed with 1.5N HCl (45 ml) and water (45 ml), dried and evaporated to dryness to give a solid residue (0.750 g This was purified by flash column chromatography eluting with 10% MeOH in DCM to give the title compound as a white powder (0.228 g, 26% yield). LC-ESI-HRMS of [M + H] + shows 431.106 Da. Calculated value 431.105698 Da, deviation 0.7 ppm.

2,4-Dichloro-6-[(4-methyl-2-morpholin-4-yl-thiazole-5-carbonyl) -amino] -benzoic acid (35)
To a stirred suspension of commercial 4-methyl-2-morpholin-4-yl-thiazole-5-carboxylic acid (0.4086 g, 1 eq) in DCM (30 ml) was added excess oxalyl chloride (1. 5 ml) is added dropwise at 0 ° C., followed by 1-2 drops of dry DMF. The resulting yellow solution is allowed to naturally reach room temperature and then stirred on the TLC at room temperature until the starting material has completely disappeared (˜3 hours). The mixture is then evaporated to dryness under vacuum and the residue is dissolved in DCM and washed with cold aqueous NaHCO ₃ solution. The organic phase was dried over MgSO ₄ and evaporated to dryness to give 0.440 g (yield˜100%) of 4-methyl-2-morpholin-4-yl-thiazole-5-carbonyl chloride. Is dissolved in TOL (20 ml) and Py (1.5 ml) under nitrogen. The new solution is ice-cooled and 2-amino-4,6-dichloro-benzoic acid (0.295 g, 0.8 eq) (Journal of Organic Chemistry 1956 21 (171-173) as described by Sheibley et al. And the stirring is continued overnight at room temperature under nitrogen. The reaction mixture is evaporated to dryness and the crude solid residue is purified by crystallization from DMSO / water (0.256 g, 34% yield). LC-MS of [M-H]-: 414.

(Example 2)
Bioactivity In this example, compound 2 (FIGS. 1A and 1B), compound 1 (FIGS. 2A and 2B) and compound 9 were used using BK channels that are heterogeneously expressed in Xenopus laevis oocytes. BK channel opening activity of (FIGS. 3A and 3B) is measured.

  A conventional two-electrode voltage clamp is used to measure the current through the BK channel. The BK current is activated by repeating the lamp protocol. Briefly, the membrane potential is continuously changed from -120 mV to +120 mV within 2 seconds. The threshold for BK activation is approximately +30 mV under control conditions. The compound is applied for 100 seconds, during which time the ramp protocol is repeated 10 times at 10 second intervals. In the middle of this ramp protocol, the membrane potential is clamped at -80 mV. Three applications of the first compound are control blanks that stabilize the current level. In the subsequent 8 applications, increasing concentrations of the compound (0.01-31.6 μM) were applied and a significant increase in current level at the depolarization potential was observed.

To assess the ability of these compounds to shift the BK activation curve to lower membrane potentials, Ohm's law g = I / (E _memb −E _rev ), where g is conductance and I is Current, E _memb is the membrane potential, and E _rev is the inversion potential) to convert the BK current to conductance. These experimental extracellular solutions contain K ⁺ 2.5 mM and the intracellular K ⁺ concentration of the oocyte is estimated to be 100 mM. Under these conditions, the Nernst equation predicts the reversal potential E _rev = −93.2 mV. The reference conductance level at the membrane potential +100 mV was calculated and the effect of the compound was evaluated as the potential difference ΔV relative to the membrane potential at which the same conductance level was obtained in the presence of the compound.

The concentration response curve for this potential difference is a sigmoidal formula: ΔV = ΔV _max / (1+ (EC ₅₀ / [compound]) ⁿ ), where ΔV _max represents the maximum left shift of the BK activation curve. , EC ₅₀ is the concentration that produces a half-maximal response, and n is the slope factor).

EC50 calculations for compounds 1, 2 and 9 are 4.4 μM, 2.4 μM and 0.97 μM, respectively. The corresponding ΔV _max values for the three compounds are −88 mV, −94 mV and −99 mV, respectively.

Claims (12)

Aromatic heterocyclic carboxylic acid amide derivatives of formula I

(Where
X is alkyl, cycloalkyl, alkenyl, alkynyl, methoxyiminomethyl, amino, N-alkyl-amino, N, N-dialkyl-amino, N-aryl-amino, N, N-diaryl-amino, alkyl-sulfonyl- 5-membered selected from amino, aryl-sulfonyl-amino, alkyl-carbonyl-amino, aryl-carbonyl-amino, phenyl or imidazolyl, 2-oxopyrrolidin-1-yl, piperidinyl, morpholin-4-yl and pyridinyl Represents a 6-membered heterocyclic group, and these phenyl and heterocyclic groups are one or more times with a substituent selected from the group consisting of alkyl, halo, trifluoromethyl, cyano, hydroxy, phenyl and alkoxy-carbonyl Has been replaced by;
L is absent (ie represents a covalent bond) or represents a linking group —CH ₂ — or —CONH—;
HET represents a 5-membered aromatic heterocyclic group selected from furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl and triazolyl, which heterocyclic group is selected from the group consisting of alkyl, halo, trifluoromethyl and cyano Optionally substituted one or more times with a substituent;
R ¹ is tetrazolyl, tetrazolyl-alkoxy, N-phenyl-carbamoyl, alkyl-sulfonyl-amino-carbonyl, N-alkyl-sulfonyl-carboxamide, N-phenyl-sulfonyl-carboxamide, carboxy, N-cyano-carboxamide, sulfamoyl, Sulfonic acids, sulfonic acid alkyl esters, sulfonic acid phenyl esters, or 5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl and 5-thioxo-4,5-dihydro- [ Represents an oxadiazolyloxo- or thio-derivative selected from 1,2,4] oxadiazol-3-yl;
R ² represents halo or trifluoromethyl;
R ³ represents hydrogen, halo, trifluoromethyl, amino, N-alkyl-amino, N, N-dialkyl-amino, piperidinyl or morpholinyl), a stereoisomer or a mixture of stereoisomers thereof, or a medicament thereof Acceptable addition salt.   X is alkyl, cycloalkyl, alkenyl, alkynyl, methoxy-iminomethyl, amino, N-alkyl-amino, N, N-dialkyl-amino, N-aryl-amino, N, N-diaryl-amino, alkyl-sulfonyl- 5-membered selected from amino, aryl-sulfonyl-amino, alkyl-carbonyl-amino, aryl-carbonyl-amino, phenyl or imidazolyl, 2-oxopyrrolidin-1-yl, piperidinyl, morpholin-4-yl and pyridinyl Represents a 6-membered heterocyclic group, and these phenyl and heterocyclic groups are one or more times with a substituent selected from the group consisting of alkyl, halo, trifluoromethyl, cyano, hydroxy, phenyl and alkoxy-carbonyl Replaced by, billed Aromatic heterocyclic carboxylic acid amide derivative according to 1, or additional pharmaceutically acceptable salt thereof. L is absent (i.e., represents a covalent bond), or a linking group -CH 2 _- or represents a -CONH-, aromatic heterocyclic carboxylic acid amide derivative according to claim 1 or 2, or a pharmaceutically As an acceptable addition salt.   HET represents a 5-membered aromatic heterocyclic group selected from furanyl, thienyl, oxazolyl, thiazolyl, pyrazolyl and triazolyl, the heterocyclic group being selected from the group consisting of alkyl, halo and trifluoromethyl The aromatic heterocyclic carboxylic acid amide derivative according to any one of claims 1 to 3, or a pharmaceutically acceptable addition salt thereof, which is optionally substituted once or multiple times. R ¹ is tetrazolyl, tetrazolyl-alkoxy, N-phenyl-carbamoyl, alkyl-sulfonyl-amino-carbonyl, N-alkyl-sulfonyl-carboxamide, N-phenyl-sulfonyl-carboxamide, carboxy, N-cyano-carboxamide, sulfamoyl, Sulfonic acids, sulfonic acid alkyl esters, sulfonic acid phenyl esters, or 5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl and 5-thioxo-4,5-dihydro- [ Aromatic heterocyclic carboxylic acid according to any one of claims 1 to 4, which represents an oxadiazolyloxo- or thio-derivative selected from 1,2,4] oxadiazol-3-yl. Amide derivatives, or pharmaceutically acceptable addition salts thereof. The aromatic heterocyclic carboxylic acid amide derivative according to any one of claims 1 to 5, or a pharmaceutically acceptable addition salt thereof, wherein R ² represents halo or trifluoromethyl. R ³ is hydrogen, halo, trifluoromethyl, amino, N- alkyl - amino, N, N- dialkyl - amino, represents a piperidinyl or morpholinyl, aromatic according to any one of claims 1 to 6 Heterocyclic carboxylic acid amide derivatives, or pharmaceutically acceptable addition salts thereof. 5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
1- (4-Chloro-phenyl) -5-trifluoromethyl-1H-pyrazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
1- (4-Bromo-benzyl) -5-methyl-1H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide ;
5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid (5-chloro-2-phenylcarbamoyl-phenyl) -amide;
5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid (5-chloro-2-methanesulfonylaminocarbonyl-phenyl) -amide;
4-chloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzenesulfonic acid;
5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (1H-tetrazol-5-ylmethoxy) -phenyl] -amide;
4,5-dichloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzenesulfonic acid;
4-methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
4-chloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzoic acid;
4-chloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzoylcyanamide;
5- (4-chloro-phenyl) -2-methyl-furan-3-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -4,5-difluoro-benzoic acid;
4,5-dichloro-2-{[5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carbonyl] -amino} -benzenesulfonic acid methyl ester;
5-methyl-2-phenyl-2H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
5-trifluoromethyl-2- (4-trifluoromethyl-phenyl) -oxazole-4-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxa Diazol-3-yl) -phenyl] -amide;
5-trifluoromethyl-2- (4-trifluoromethyl-phenyl) -oxazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole) -3-yl) -phenyl] -amide;
5- (4-chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [4,5-dichloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
5- (4-Chloro-phenyl) -2-methyl-furan-3-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole-3 -Yl) -phenyl] -amide;
2- (4-Chloro-benzyl) -thiazole-4-carboxylic acid [5-chloro-2- (5-oxo-2,5-dihydro- [1,2,4] oxadiazol-3-yl)- Phenyl] -amide;
1- (4-Bromo-benzyl) -5-methyl-1H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1, 2,4] oxadiazol-3-yl) -phenyl] -amide;
4-Methyl-2-morpholin-4-yl-thiazole-5-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl) ) -Phenyl] -amide;
4-methyl-2-morpholin-4-yl-thiazole-5-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
2- (3-Chloro-phenyl) -5-methyl-2H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1, 2,4] oxadiazol-3-yl) -phenyl] -amide;
4- {5- [5-Chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazol-3-yl) -phenylcarbamoyl] -4-methyl-thiazole-2 -Yl} -piperidine-1-carboxylic acid tert-butyl ester;
4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole) -3-yl) -phenyl] -amide;
5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-4-morpholin-4-yl-2- (5-oxo-4,5-dihydro- [1 , 2,4] oxadiazol-3-yl) -phenyl] -amide;
5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-4-dimethylamino-2- (5-oxo-4,5-dihydro- [1,2, 4] oxadiazol-3-yl) -phenyl] -amide;
5- (4-Chloro-phenyl) -2-trifluoromethyl-furan-3-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole) -3-yl) -4-piperidin-1-yl-phenyl] -amide;
2- (3-Chloro-phenyl) -5-methyl-2H- [1,2,3] triazole-4-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide ;
4-methyl-2-pyridin-4-yl-thiazole-5-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide;
4-Methyl-2- (4-trifluoromethyl-phenyl) -thiazole-5-carboxylic acid [5-chloro-2- (5-oxo-4,5-dihydro- [1,2,4] oxadiazole) -3-yl) -4-piperidin-1-yl-phenyl] -amide;
5- (cyclopentanecarbonyl-amino) -3-methyl-thiophene-2-carboxylic acid [5-chloro-2- (1H-tetrazol-5-yl) -phenyl] -amide; or 2,4-dichloro-6 -[(4-Methyl-2-morpholin-4-yl-thiazole-5-carbonyl) -amino] -benzoic acid;
The aromatic heterocyclic carboxylic acid amide derivative according to claim 1, or a pharmaceutically acceptable addition salt thereof.   A therapeutically effective amount of the aromatic heterocyclic carboxylic acid amide derivative according to any one of claims 1 to 8, or a pharmaceutically acceptable addition salt thereof or a prodrug thereof, one or more adjuvants, A pharmaceutical composition comprising an excipient, carrier and / or diluent.   9. A pharmaceutical composition / drug for the manufacture, treatment or prevention or alleviation of a disease or disorder or condition responsive to modulation of potassium channels in mammals including humans. Or the use of a pharmaceutically acceptable addition salt thereof.   The disease, disorder or condition is respiratory disease, epilepsy, convulsions, seizures, absence seizures, vasospasm, coronary artery spasms, motor neuron diseases, myopathies, kidney disease, polycystic kidney disease, bladder overexcitation, Bladder spasticity, genitourinary disorder, urinary incontinence, bladder outflow inhibition, erectile dysfunction, gastrointestinal dysfunction, gastrointestinal dysmotility disorder, gastrointestinal motility dysfunction, postoperative ileus obstruction, constipation, gastroesophageal reflux disorder, secretory diarrhea, obstructive Or inflammatory airway disease, ischemia, cerebral ischemia, ischemic heart disease, angina, coronary heart disease, ataxia, traumatic brain injury, stroke, Parkinson's disease, bipolar disorder, psychosis, schizophrenia, Autism, anxiety, mood disorder, depression, manic depression, psychotic disorder, dementia, learning deficits, age-related memory forgetfulness, memory and attention deficit, Alzheimer's disease, amyotrophic lateral sclerosis ( ALS), dysmenorrhea, sleep seizures, sleep Disorder, sleep apnea, Raynaud's disease, intermittent claudication, Sjogren's syndrome, dry mouth, cardiovascular disorder, hypertension, myotonic dystrophy, myotonic dystrophy, spasticity, dry mouth, type II Diabetes, hyperinsulinemia, premature birth, cancer, brain tumor, inflammatory bowel disease, irritable bowel syndrome, colitis, Crohn's disease, immunosuppression, hearing loss, migraine, pain, neuropathic pain, inflammatory pain Use according to claim 10, which is trigeminal neuralgia, visual impairment, rhinorrhea, ocular hypertension (glaucoma) or alopecia. A method of treating, preventing or alleviating a disease or disorder or condition in an animal organism, including a human, that is responsive to modulation of potassium channels, wherein the animal organism in need thereof has a therapeutically effective amount of 9. A method as claimed in claim 1, comprising the step of administering the aromatic heterocyclic carboxylic acid amide derivative according to any one of claims 1-8.

Images